Women s Health Matters

Transcription

1 Wmen s Health Matters Nutritin & Breast Cancer Natalie Ledesma, MS, RD, CSO Ida & Jseph Friend Cancer Resurce Center UCSF Helen Diller Family Cmprehensive Cancer Center University f Califrnia, San Francisc Gd nutritin may reduce the incidence f breast cancer and the risk f breast cancer prgressin r recurrence. There are many studies in prgress t help further understand hw diet and cancer are related. We d knw, hwever, that imprved nutritin reduces risk f chrnic diseases, such as diabetes, besity, hypertensin and heart disease, and als enhances verall quality f life. It is estimated that ne third f cancer deaths in the U.S. can be attributed t diet in adulthd [1]. Guidelines fr a Healthy Diet Plant-based diet Plenty f fruits and vegetables High fiber beans/legumes, seeds, whle grains Include prtein with every meal - aim t include plant prtein daily Lw/mderate fat diet with emphasis n healthy fats Revised 07/15 Limit prcessed and refined grains/flurs/sugars Drink plenty f fluids Be physically active t help achieve and/r maintain a healthy weight Plant based diet A lifelng cmmitment t a plant based diet may lwer a wman s risk f develping breast cancer and may als reduce the risk f recurrent breast cancer. A plant based diet cnsists primarily f fruits, vegetables, beans/legumes, nuts/seeds and whle grains. A large chrt* study with ver 91,000 wmen shwed a plant-based diet was assciated with a 15% reductin in breast cancer risk; this effect was even mre significant fr thse with estrgen-receptr negative and prgesterne-receptr negative (ER-/PR-) tumrs [2]. Similarly, fllwing a Mediterranean dietary pattern f vegetables, fish and live il, legumes, and fruit was independently assciated with a decreased risk f breast cancer [3]. * All wrds nted with an asterisk ( * ) are defined in the glssary n page 54. Healthy Plate Diagram Fill yur plate with apprximately 50% (r mre) vegetables, 25% (r mre) prtein, and up t 25% starchy vegetable r whle grain. Find a Dctr: (888) Patient Educatin Library:

2 SUMMARY - HEALTHY BREAST CANCER DIET Eat 8 t 10 clrful fruit and vegetable servings daily Tw t three pieces f fruit One cup r mre f vegetables with lunch and dinner 8 fl z vegetable juice Cnsume 30 t 45 grams f fiber daily Yu will likely meet yur fiber gal if yu eat 8 t 10 servings f fruits and vegetables plus ne serving f beans/legumes, ne serving f chia and/r flax seed, r at least tw servings f whle grains daily. Avid prcessed and refined grains/flurs/sugar Keep WHITE ff yur plate: bread, pasta, rice, cream sauces, cakes, and mre. Lean prtein with every meal; plant prtein daily Limit fatty & prcessed meats, and dairy Include healthy fats like cld-water fish, chia seeds, flaxseeds, walnuts, sybeans, live il, avcads Eat chia seeds and grund flax daily 1-2 Tbsp daily Cnsume herbs and spices daily Limit alchl cnsumptin Drink 1 t 4 cups f green tea daily Ask yur dctr abut having a vitamin D bld test (serum 25 (OH)-vitamin D level). Maintain yur level abve 40 ng/ml thrugh diet and, if needed, supplements Drink plenty f fluids, water r nn-caffeinated beverages, daily t help meet fluid needs Engage in daily physical activity t help achieve and/r maintain a healthy weight FRUITS AND VEGETABLES Cntain vitamins, minerals, fiber, and varius cancer-fighting phytnutrients* (fr example: cartenids, lycpene, indles, isflavnes, flavnls). Vibrant, intense COLOR is ne indicatr f phytnutrient* cntent. There is extensive and cnsistent evidence that diets high in fruits and vegetables are assciated with decreased risks f many cancers, and while results fr breast cancer risk are nt yet cnclusive, they are prmising [2-26]. In a study f abut 3,000 pstmenpausal wmen, a prtective effect fr vegetables was bserved [4]. Wmen wh cnsumed 25 r mre servings f vegetables weekly had a 37% lwer risk f breast cancer cmpared with wmen wh cnsumed fewer than 9 vegetable servings weekly. 2

3 An epidemilgical* study reprted a significant prtective effect f vegetables against breast cancer when case-cntrl* and chrt* studies were cnsidered tgether [6]. A meta-analysis* lking at the data frm 17 studies [27] revealed that high vs. lw vegetable cnsumptin was assciated with a 25% reductin in breast cancer risk, but these findings were nt cnfirmed by data cllected frm 8 studies [28]. A study f ver 31,000 wmen shwed an inverse assciatin between vegetable cnsumptin and breast cancer risk [23]. Vegetables f nte were leafy vegetables, fruiting vegetables (peppers, tmates, eggplant), and raw tmates. In a chrt* study f nearly 21,000 participants, high cnsumptin f fruit and salad was assciated with a reduced risk f breast cancer, particularly in ER-/PR- tumrs [15]. A recent case-cntrl* study reprted wmen wh cnsumed mre than 3.8 servings f fruits and vegetables daily had a lwer risk f breast cancer when cmpared with wmen wh cnsumed fewer than 2.3 daily servings [29]. Japanese wmen fllwing a prudent dietary pattern (high in fruits and vegetables, lw in fat) had a 27% decreased risk f breast cancer [7]. A diet characterized by vegetables, fruit, and sy lwered risk f breast cancer amng pstmenpausal wmen by 30%; this effect was even strnger (43% risk reductin) fr thse fllwing this diet pattern fr 5 r mre years [17]. A Krean case-cntrl* study reprted that a high intake f certain fruits and vegetables resulted in a significantly lwer risk f breast cancer in premenpausal (tmates) and pstmenpausal wmen (grapes and green peppers) [8]. Pickled vegetables, hwever, may increase breast cancer risk [24]. A meta-analysis f 12 studies cncluded that the risk f breast cancer decreased significantly in wmen with a high flavnl and flavne intake [22]. Flavnl-rich fds include nins, kale, leeks, and brccli and flavne-rich fds include parsley, thyme, celery, regan, and chili peppers. A prspective analysis that included mre than 75,000 wmen ver a perid f 24 years, reprted the fllwing: 18% reduced risk f ER- breast cancer in wmen wh cnsumed 2 servings f berries weekly 31% reduced risk f ER- breast cancer in wmen wh cnsumed 1 r mre servings f blueberries weekly 41% risk reductin f ER- breast cancer in wmen wh cnsumed 2 servings f peaches/ nectarines weekly [19] Limnene, a biactive fd cmpnent frm citrus peel il may lead t cell-cycle arrest and reduced cell prliferatin in breast tissue [30]. While n effect was bserved fr vegetables, increasing ttal fruit intake significantly lwered the risk f breast cancer when cmparing thse in the highest t lwest tertile [31]. This effect was greater fr thse with ER+ tumrs. Eating a salad vegetable dietary pattern (high cnsumptin f raw vegetables and live il) exerted a significant prtective effect against HER-2-psitive cancers [12]. 3

4 This study fund that while specific vegetables (carrts and cruciferus vegetables) may be prtective fr all breast cancer types, ttal vegetable cnsumptin was assciated with a decreased risk f ER-/PR- breast cancer types nly [32]. In a case-cntrl* study f 6,917 Chinese wmen, ttal vegetable intake was inversely related t breast cancer risk, as were high intake f citrus and rsaceae fruits (apples, pears, quinces, apricts, plums, cherries, peaches, raspberries, lquats, and strawberries); n difference was bserved between different tumr types [16]. The Dietary Appraches t Stp Hypertensin (DASH) diet was assciated with a significantly lwer risk f ER- breast cancer; this effect was largely explained by higher intakes f fruits and vegetables [33]. A vegetable-based, lw-carbhydrate-diet was als assciated with a significantly lwer risk f ER- breast cancer. N assciatin was fund between ER+ tumrs and fruit and vegetable intakes. A study assessing plasma r bld cartenids as a marker fr fruit and vegetable intake reprted that individuals in the tp 1/4 had a 43% lwer risk f breast cancer recurrence when cmpared t thse in the lwest 1/4 [34]. Hwever, n assciatin was bserved between fruit and vegetable cnsumptin and breast cancer recurrence when wmen cnsumed five servings daily vs. eight servings daily [35]. Breast cancer survivrs significantly reduced mrtality by fllwing a diet lw in fat, high in vegetables, high in fiber, and high in fruit [36]. The cmbinatin f cnsuming five r mre daily servings f vegetables and fruits, and accumulating 540+ metablic equivalent tasks-min/wk (equivalent t walking 30 minutes 6 d/wk) decreased mrtality by nearly 50% [13]. The effect was strnger in wmen wh had ER+ r PR+ cancers. Vegetable intake has been inversely assciated with serum insulin-like grwth factr-i (IGF-I) levels [37]. IGF-I levels have been directly assciated with breast cancer. Beta-Cartene Beta-cartene is ne f the 600 cartenids that can be partially cnverted int vitamin A in the bdy. Cartenids have a prtective rle fr certain sites, including breast cancer [9, 38-41]. Cartenid intake was significantly assciated with reduced mrtality in breast cancer survivrs [36]. In varius studies, serum beta-cartene levels were lwer amng breast cancer patients cmpared t wmen withut cancer [38, 42-49]. One f these studies reprted the risk f breast cancer t be 221% greater fr wmen in the lwest quartile f serum beta-cartene cmpared t wmen in the highest quartile [29]. This inverse assciatin was strnger fr ER- tumrs than ER+ tumrs [48]. A case-cntrl* study reprted that increased plasma levels f beta-cartene, retinl, and ttal antixidant* status were assciated with abut a 50% reduced risk f breast cancer [45]. Cell studies indicate that cartenids may inhibit the prductin f breast cancer cells [50-51]. Beta-cartene may inhibit ER+ and ER- breast tumr develpment [39]. 4

5 Beta-cartene may hinder the develpment f breast cancer cells by inhibiting cell prliferatin [52], arresting cell cycle [52], and inducing apptsis* [52-53]. Research indicates that dietary surces f beta-cartene are likely much mre prtective than supplemental surces against the risk f cancer [54-56]. Cnsuming higher amunts f dietary beta-cartene, lycpene, and beta-cryptxanthin was assciated with a lwer risk f breast cancer amng Chinese wmen [40]. Carrt intake was inversely assciated with risk f breast cancer in the Black Wmen s Health Study [32]. Dietary cnsumptin f alpha-cartene, beta-cartene, beta-cryptxanthin, and lutein/zeaxanthin were all assciated with a lwer risk f breast cancer [57] in ER- breast cancer nly [58]. Lycpene, hwever, did nt result in a reductin f breast cancer risk. Dietary alpha-cartene, beta-cartene, and lycpene were inversely assciated with risk f ER+/ PR+ breast cancer [41]. Dietary beta-cartene intake was inversely assciated with IGF-I levels in a large case-cntrl study [37]. Cruciferus Vegetables Sme evidence suggests that the cruciferus vegetables, in particular, are assciated with a reduced risk f breast cancer [32, 59-65]. A recent meta-analysis* f 13 epidemilgic studies indicated that high cruciferus vegetable intake was significantly assciated with a reduced risk f breast cancer [66]. A Swedish study f pstmenpausal wmen reprted ne t tw daily servings f cruciferus vegetables reduced the risk f breast cancer, pssibly by as much as 20-40% [62]. Cruciferus vegetable intake was assciated with a significant decrease in risk f breast cancer in Japanese premenpausal wmen [60]. N significant assciatin was bserved fr pstmenpausal wmen and breast cancer. Wmen wh ate mre turnips and Chinese Cabbage (bth in the cruciferus vegetable family) significantly reduced the risk f pstmenpausal breast cancer [65]. Cnsumptin f cruciferus vegetables, particularly brccli, was inversely assciated, thugh nt statistically significant, with breast cancer risk in wmen [61]. The U.S. cmpnent f the Plish Wmen s Health Study fund that wmen wh cnsumed raw- r shrt-cked cabbage and sauerkraut 3 r mre times weekly had a significantly reduced risk f breast cancer [64]. Cabbage that was cked fr a lng time had n effect n breast cancer risk. Researchers suggested that glucsinlates, cmpunds in cabbage, may affect bth the initiatin phase f carcingenesis*, cell mutatin*, and inhibit apptsis*. Cruciferus vegetables appear t shift estrgen metablism in a favrable manner; increasing 2-hydrxyestrne:16-a-hydrxyestrne [67-68]. Fwke and clleagues [68] cncluded that cnsuming mre cruciferus vegetables acrss the ppulatin may have an impact n the incidence f breast cancer. 5

6 Several studies suggest that cmpunds fund in these fds, isthicyanates (sulfraphane), have inhibitry effects n breast cancer cells in bth cell studies and animal studies [59, 63, 69-71]. One mechanism appears t be thrugh ptent inhibitin f phase I and inductin f phase II detxifying enzymes, such as glutathine-s-perxidase [61, 65, 70]. Furthermre, these cmpunds reduced cell prliferatin and inhibited cyclxygenase-2 (COX- 2) expressin in breast cancer cells [72]. Inhibited cell grwth and induced apptsis has als been bserved [73]. Human breast cancer stem cells decreased significantly when benzyl isthicyanate was intrduced int the diet [69]. Indle-3-carbinl (I3C) is a cmpund fund in cruciferus vegetables that has anticancer prperties and anti-prliferative effects n breast cancer cells [74]. I3C may inhibit the grwth f bld vessels that the tumr needs t grw (anti-angigenesis) [75]. I3C and diindlylmethane (DIM) induce apptsis*, r cell death, in breast cancer cells [67,76] fr bth ER+ and ER- tumr cells [77]. Furthermre, I3C and tamxifen have been shwn t act separately and/r cperatively t inhibit the grwth f ER+ breast cancer cells [78]. Dietary I3C may have effects that blster immune functin [79]. Anther cmpund in cruciferus vegetables, calcium-d-glucarate, has been shwn t inhibit betaglucurnidase, an enzyme invlved in phase II liver detxificatin. Elevated beta-glucurnidase activity is assciated with an increased risk fr varius cancers, particularly hrmne-dependent cancers such as breast cancer [80]. Pmegranate (Punica granatum; Punicaceae) Varius parts f the pmegranate fruit (fr example: seed il, juice, fermented juice and peel extract) have expressed suppressive effects n human breast cancer cells in labratry research [81]. Pmegranate seed il and fermented juice blck the cancer cells xygen supply, slw cell grwth, and prmte cell death [82]. Fermented pmegranate juice plyphenls* appear t have twice the anti-prliferative effect as fresh pmegranate juice plyphenls* [83]. Pmegranate husk, rich in ellagitannins (plyphenls*), exhibited strng anti-prliferative activity against breast cancer cell lines and inhibits xidative DNA damage [84]. Pmegranate juice, r a cmbinatin f its cmpnents (lutelin, ellagic acid, punicic acid) increase cancer cell adhesin and decrease migratin, while leaving nrmal cells unaffected [85]. Furthermre, ne study suggests that pmegranate seed il may have the greatest preventive activity (87% reductin in lesins) cmpared t fermented pmegranate juice (42% reductin) [86]. Pmegranate peel extract has imprtant antixidant effects, and has been shwn t inhibit human breast cancer cells and hlds prmise as a pssible treatment against breast cancer [87-89]. 6

7 Nutrient Dietary Surces Recmmendatin Beta-cartene Carrts, sweet ptates, winter squash, cantalupe, and mang Include these fruits and vegetables daily. Cruciferus vegetables Arugula, brccli, Brussels Include these vegetables daily. spruts, cabbage, cauliflwer, cllard greens, hrseradish, kale, khlrabi, mustard greens, radishes, rutabaga, turnips and turnip greens, and watercress Pmegranate Pmegranate Cnsider including pmegranate r pmegranate cncentrate n a regular basis. Organic Prduce Organic fruits and vegetables have fewer pesticides, lwer levels f ttal pesticides, and less verall pesticide txicity than fruits and vegetables grwn with chemicals. Althugh mre research is needed, recent evidence indicates a significant increase in antixidants* in rganic and sustainably grwn fds versus cnventinally grwn fds [90-95]. Organic vegetables cntained a greater cncentratin f phytnutrients* (phenlic acids) when cmpared t cnventinally grwn vegetables [92, 93]. Organic fermented beetrt juices ffered strnger anticancer activity than the cnventinal juice [95]. Additinally, rganic fresh beets cntained mre vitamin C than the cnventinal beets. The extracts frm rganically grwn strawberries had a higher cntent f antiprliferative activity fr breast cancer cells, and displayed a 43% inhibitin [96]. Cnsuming rganic fds appears t increase salicylic acid, which may cntribute t a lwer risk f cancer [92]. Pesticides such as rganchlrine cmpunds (OCC), knwn as envirnmental pllutants, have been implicated in the etilgy f estrgen-related disrders due t their ptential estrgenic and anti-estrgenic prperties [94]. Results f sme studies [94, 97-98], but nt all [99] suggest that envirnmental expsure t rganchlrine pesticide residues r PCBs may cntribute t multifactrial pathgenesis f breast cancer. In a study f wmen living n Lng Island, New Yrk, breast cancer risk was assciated with lifetime residential pesticide use [100]. Organchlrine pesticide residues, including DDTs and HCHs, may increase wmen s risk f breast cancer, particularly in premenpausal wmen in China [97]. In mice, expsure t beta-hch, an rganchlrine pesticide residue, bth accelerated the appearance and incidence f breast cancer tumrs when cmpared t cntrls mice [98]. 7

8 The level f expsure may be integral in determining the effects f these OCC. One study fund that when breast adipse tissue reached levels higher than 2600 ppb, wmen with pstmenpausal ER+ breast cancer exhibited high prliferatin [101]. Chsing rganic prduce will help yu reduce yur levels f pesticide expsure and will mst likely increase yur phytnutrient* cnsumptin. Althugh washing and peeling yur nn-rganic fruits r vegetables may help t reduce pesticide residues, it will nt eliminate them. Listed belw are prduce with the mst and least pesticide cntaminatin, bth in terms f number f pesticides used and the level f pesticide cncentratin n an average sampling. Thus, fr the fruits and vegetables shwn n the mst cntaminated list, it is wise t buy rganic. Alternatively, if rganic chices are nt available, yu may want t cnsider substituting with prduce that tends t cntain the least amunt f pesticides. Prduce mst cntaminated by pesticides: Apples Peaches Nectarines Strawberries Grapes Celery Spinach Sweet bell peppers Cucumbers Cherry tmates Snap peas - imprted Ptates Prduce least cntaminated by pesticides: Avcads Sweet crn Pineapple Cabbage Sweet peas Onins Asparagus Mangs Papayas Kiwi Eggplant Grapefruit **Adapted frm Envirnmental Wrking Grup A Shpper s Guide t Pesticides in Prduce It is mst imprtant, hwever, t eat fruits and vegetables rganic r cnventinal. If the availability r cst f rganic prduce is a barrier, yu may wish t avid thse fruits and vegetables that have the highest pesticide residue cntent. FIBER A PLANT-BASED DIET IS NATURALLY HIGH IN FIBER A diet rich in natural fiber btained frm fruits, vegetables, legumes (fr example: lentils, split peas, black beans, pint beans), and whle-grains may reduce cancer risk and/r reduce risk f cancer prgressin. Fiber binds t txic cmpunds and carcingens, which are then later eliminated frm the bdy [102]. Varius mechanisms have been prpsed fr the prtective effects f dietary fiber against cancer. These include: Increased fecal bulk and decreased intestinal transit time, which allw less pprtunity fr fecal mutagens t interact with the intestinal epithelium [103]. Binding t bile acids, which are thught t prmte cell prliferatin [104]. 8

9 Fermentatin in the gut, prducing shrt-chain fatty acids (SCFA). SCFA imprve the gut envirnment and may prvide immune prtectin beynd the gut [103, 104]. Additinally, whle grains are rich in antixidants*, including trace minerals and phenlic cmpunds, which have been linked t disease preventin [104]. Furthermre, a high fiber diet wrks t reduce hrmne levels that may be invlved in the prgressin f breast cancer [103, ]. A high-fiber, lw-fat diet interventin fund that fiber reduced serum estradil* (estrgen breaks dwn int estradil* in the bdy) cncentratin in wmen diagnsed with breast cancer, the majrity f whm did nt exhibit weight lss. Thus, increased fiber intake was independently related t the reductin in serum estradil* cncentratin [107]. This decrease in estrgen levels in the bld thereby may ptentially reduce the risk f hrmne-related cancers, such as breast cancer. Reduced levels f serum estrne* and estradil* were bserved in premenpausal wmen with a greater intake f dietary fiber [106]. Similarly, a high intake f dietary fiber was significantly assciated with lw serum levels f estradil in pstmenpausal breast cancer survivrs [108]. Dietary fiber intake increases the amunt f estrgen excreted in the stl [109]. A high fiber diet is als assciated with less besity [105] - a risk factr fr pstmenpausal breast cancer. A high fiber diet may als lwer cancer risk via reduced inflammatin. Breast cancer survivrs wh cnsumed >15.5 g/day f insluble dietary fiber had a 49% reductin in the likelihd f having an elevated C-reactive prtein (CRP) cncentratin, a bimarker that assesses inflammatin [110]. A meta-analysis* f 10 prspective chrt studies and 16,848 cases shwed that fr every 10 g fiber/day increase, there was an assciated 7% reductin in breast cancer risk [111]. In a study f 11,576 breast cancer cases, risk was inversely linked t ttal dietary fiber intake and fiber frm vegetables [112]. The risk reductin was even mre prnunced in ER-/PR- wmen. Similarly, sluble fiber intake was assciated with a significantly reduced risk f breast cancer in pre-menpausal wmen; this effect was greatest in wmen with ER- tumrs [113]. A high fiber diet was assciated with a lwer risk f breast cancer in bth pre- and pstmenpausal wmen [114]. In a study f wmen with primary breast cancer, a significant inverse assciatin (69% reduced risk) was fund between dietary fiber and breast cancer risk in ER+, ER-, PR+, ER+PR+, and ER-PR+ tumrs [115]. Ttal dietary fiber intake, particularly frm cereals and fruit, was fund t significantly reduce the risk f breast cancer in pre-menpausal, but nt pst-menpausal wmen [116]. A recent chrt* study reprted that high fiber intake was assciated with a 42% lwer risk f pstmenpausal breast cancer, when cmparing wmen in the highest quintile f fiber intake cmpared t the lwest quintile [117]. 9

10 An earlier prspective chrt* study, hwever, reprted n prtective effect f fiber against breast cancer when cmparing wmen wh cnsumed fewer than 26 grams dietary fiber cmpared t thse wh cnsumed even less [118]. This finding is nt surprising given that the ttal grams f fiber cnsumptin was less than 30 grams. Similarly, anther study that reprted n significant findings cmpared wmen cnsuming less than 25 g fiber daily [119]. Overall, case-cntrl* studies have reprted the greater the fiber intake, the lwer the incidence f breast cancer [10, 114, ]. Data frm prspective studies is mixed, reprting prtective effects [117, ] r n effect bserved [118, 119]. Wmen wh ate beans and lentils at least twice a week had a 24% lwer risk f develping breast cancer than wmen wh ate them less than nce a mnth [126]. Mre recently, cnsumptin f legumes was fund t be inversely assciated with breast cancer [16]. High-Fiber Surces FRUITS: Fd Serving Size Fiber Grams/ Serving Apple 1 medium 3.7 Banana 1 medium 2.8 Blackberries 1/2 cup 1.9 Blueberries 1 cup 1.3 Cantalupe 1/2 cup 6.0 Figs (dried) 1/4 cup 6.0 Grapefruit 1 medium 3.4 Grapes 1 cup 1.6 Guava 1 medium 4.9 Kiwi 1 medium 2.6 Orange 1 medium 3.1 Pear 1 medium 4.0 Persimmn 1 medium 6.0 Prunes 1/4 cup

11 GRAINS & OTHER PRODUCTS: Fd Serving Size Fiber Grams/ Serving Amaranth 1/4 cup dry 7.4 Barley 1/2 cup cked 3.0 Beans, black 1/2 cup cked 8.3 Beans, red kidney 1/2 cup cked 8.2 Beans, garbanz 1/2 cup cked 5.0 Bran cereals 3/4 cup Check labels ( ) Brwn rice 1/2 cup cked 1.4 Bulgur 1/2 cup cked 4.0 Oatmeal 1/2 cup cked 2.0 Peanuts 1/4 cup 2.9 Quina 1/4 cup dry 2.5 VEGETABLES: Fd Serving Size Fiber Grams/ Serving Artichkes 1 medium 6.9 Beets 1/2 cup cked 1.7 Brccli 1/2 cup cked 2.3 Brussel spruts 1/2 cup cked 2.0 Carrts 1/2 cup cked 2.6 Kale 1/2 cup cked 1.3 Lima beans 1/2 cup cked 4.5 Peas, green 1/2 cup cked 4.4 Spinach 1/2 cup cked 2.2 Squash, winter-type 1/2 cup cked 3.4 Sweet ptates (yams) 1/2 cup cked 2.7 SUGARS AND THE ROLE OF INSULIN* High sugar fds are usually highly prcessed and refined, lw in nutrient value, and als lw in dietary fiber. In additin, these fds appear t increase serum insulin* and serum insulin-like grwth factr (IGF-I) levels [127], which stimulate cancer cell grwth. Overexpressin, r high amunts, f IGF increases mammary tumrs in mice [128]. IGF s may wrk by stimulating cell cycle prgressin and prevent cells frm premature death [ ]. IGF-I may prmte tumr grwth via upregulatin f varian sterid secretin [ ]. Research indicates a synergistic effect between IGF-I and estrgen [134] as well as IGF-I and insulin* resistance [135] in breast cancer. 11

12 Wmen in the highest quintile f IGF-I level had a 310% increased risk f all-cause mrtality [136]. A prspective chrt* study bserved a significant 310% increased risk f breast cancer in premenpausal wmen wh had the highest quartile f IGF-I cmpared t wmen with the lwest quartile [132]. A weaker assciatin was fund with fasting insulin* levels where premenpausal wmen in the tw highest quartiles had a 70% greater risk fr breast cancer. In premenpausal wmen, wmen in the highest quartile f serum glucse had a 280% increased risk f breast cancer cmpared with wmen in the lwest quartile. In pstmenpausal wmen, the assciatins f glucse, insulin*, and IGF-I were assciated with breast cancer risk in heavier subjects (BMI>26 1 ). Overall, these findings indicate that chrnic change f glucse/sugar metablism is related t breast cancer develpment. Other studies supprt a strnger link between IGF-I and breast cancer in premenpausal wmen [131, 137]. Additinally, a case-cntrl* study in China fund that IGF-I significantly increased the risk f breast cancer [135]. IGF-I levels were psitively assciated with the risk f ER+ breast tumrs (pre- and pstmenpausal wmen cmbined) and amng wmen wh were diagnsed with breast cancer at 50 years r lder [138]. Nnetheless, a meta-analysis* review f 18 studies reprted n verall statistically significant assciatin between circulating IGF-I levels and risk f breast cancer althugh the levels were greater in breast cancer patients than cntrls [130]. Hwever, IGF-I levels did appear t increase breast cancer risk in premenpausal wmen by almst 40%. Similarly, a large prspective trial reprted IGF-I significantly increased risk f breast cancer in premenpausal wmen under the age f 50; n significant relatinship was nted fr pstmenpausal wmen [139]. It has been suggested that decreasing IGF-I levels may be ne factr that cntributes t tamxifen s anti-tumr activity in breast cancer therapy [140]. While nt all studies [141] agree, a chrt* study reprted that higher insulin* levels significantly increased risk f breast cancer fr bth pre- and pst-menpausal wmen [142]. Recent studies indicate that high insulin* levels, increased cncentratin f IGF-I, and greater abdminal fat are assciated with increased risk fr breast cancer [143]. One study nted a direct assciatin, thugh nt statistically significant, between nn-fasting serum insulin* levels and 10-year mrtality in pstmenpausal breast cancer wmen [144]. Amng ther factrs, a diet lw in fiber may favr the develpment f insulin* resistance and hyperinsulinemia [127]. Hyperinsulinemia may cntribute t the develpment f breast cancer in verweight r bese wmen [145]. 1 BMI refers t bdy mass index, which is calculated by bdy weight (kg)/height2(m2). 12

13 Additinally, besity and fasting hyperinsulinemia have been assciated with a prer prgnsis in wmen with established breast cancer [146]. A case-cntrl* study reprted that carbhydrate intake significantly increased risk f breast cancer; sucrse (table sugar) imparted the greatest risk [147]. This risk was lessened cnsiderably with a higher fiber intake. A significant tw fld increased risk f breast cancer was assciated with wmen cnsuming the highest amunt f sugar in the diet [114]. Sugar and dessert intake was assciated with an increased risk f breast cancer [18]. Furthermre, an Italian case-cntrl* study fund that wmen wh cnsumed the highest tertile f desserts and sugars had a 19% increased risk f breast cancer cmpared with wmen in the lwest tertile [148]. A crss-sectinal study f wmen shwed that fr increasing amunts f sugar-sweetened beverages, higher mammgraphic density ccurs--a strng breast cancer risk factr [149]. A case-cntrl* study f 1,434 cases shwed that cnsumptin f sweet beverages, added sugars, and desserts was psitively assciated with breast cancer risk [150]. The risks f distant metastasis and breast cancer deaths were significantly higher in wmen with higher fasting glucse levels cmpared t wmen in the lwest glucse quintile (reference <87 mg/ dl) [152]. Breast cancer mrtality was significantly greater in ER+/PR+ wmen with a higher bld glucse (> 94 mg/dl) cmpared with thse with nrmal glucse levels [153]. The cnsumptin f sweet fds with a high glycemic index* (GI) and glycemic lad* (GL) have been implicated as a risk factr fr breast cancer due t their effects n insulin and IGF-I [ ]. Wmen wh cnsumed the greatest intake f desserts (including biscuits, briches, cakes, puffs and ice-cream) and sugars (including sugar, hney, jam, marmalade and chclate) had a 19% increased risk f breast cancer cmpared with wmen wh cnsumed the least desserts and sugars [153]. Adding credence t the idea that bld sugar levels may affect disease prgressin, wmen wh cnsumed a high GI and GL diet had a 57% and 253% increased risk f breast cancer, respectively [154]. This effect was mst prnunced in premenpausal wmen and thse wmen at a healthy bdy weight. GI and GL were bth assciated with an increased risk f breast cancer amng pstmenpausal verweight wmen; this effect was mst prnunced fr wmen with ER- breast cancer [155]. GL was psitively assciated with verall breast cancer risk in tw chrt* studies [ ]. This evidence was further supprted by a meta-analysis* that reprted GI t mdestly increase the risk f breast cancer [156]. 13

14 INSULIN HIGH TIDE. The bserved link between besity and cancer may be explained by the grwthprmting activities f insulin and IGF-1. One thery psits that excess weight sets ff a bichemical cascade that increases insulin and, in turn, IGF-1 levels. Bth hrmnes may activate IGF-1 receptrs n cells, which can spur cell grwth and inhibit cell death pathways that usually prtect against tumr develpment. E. Rell/Surce: Nature Reviews Cancer, 2004 Sugars & Insulin* Bttm Line T help cntrl yur insulin* level: Eat a high-fiber diet with limited refined/prcessed fds Fllw a lw/mderate fat diet rich in mega-3 fatty acids When yu eat fds rich in carbhydrates, include prtein at same meal/snack Limit r avid alchl Exercise Maintain a healthy bdy weight LOW FAT DIET Many studies have investigated the relatinship f fat and the risk f breast cancer, but the results remain incnsistent. Hwever, several trials shwed sme prmise in the area. The Wmen s Interventin Nutritin Study (WINS) fund that a reduced fat intake imprves relapse-free survival by 24% in pstmenpausal wmen with breast cancer cmpared with wmen fllwing a standard diet [159]. The risk f recurrence fr wmen with ER- breast cancer decreased by 42%. Later, the Eurpean Prspective Investigatin int Nutritin and Cancer (EPIC) Study reprted that eating a higher fat diet significantly increased the risk f breast cancer; wmen wh had a 35% and 39% fat diet were at a greater risk than thse eating a 31% fat diet [160]. While this diet wuld nt be cnsidered lw fat, a significant effect was still bserved. While the Nurses' Health Study fund that ttal fat intake was nt assciated with breast cancer risk [161], a systematic review and meta-analysis* reprted that increased fat in the diet was assciated with an increased risk f breast cancer [21]. Furthermre, a prspective trial suggested that a high fat diet was assciated with increased risk in ER+/PR+ disease, but nt ER-/PR- tumrs [162]. 14

15 The ptential elevated cancer risk may be, in part, due t the fact that a high fat diet stimulates increased estrgen levels, which is assciated with breast cancer grwth. A study f adlescent females fund that mdest reductins in fat intake during puberty resulted in significantly lwer cncentratins f sex hrmnes (estradil*, estrne*, prgesterne) [163]. Further research is needed t determine if in fact these lwer levels lead t a reduced risk f breast cancer. Aim fr clse t 20-30% f yur ttal calries frm fat, with less than 8% f ttal calries frm saturated fat. Likely mre imprtant, research indicates that the type f fat may be f paramunt significance. Saturated Fats Several studies indicate a psitive assciatin between saturated fat intake frm meat and dairy prducts (animal surces) and cancer [ ]. While breast cancer research is incnclusive, it is grwing [161, ]. A systematic literature review cncluded that higher saturated fat intake prediagnsis was assciated with an increased risk f breast cancer-specific mrtality [170]. Ttal saturated fatty acid intake was significantly assciated with breast cancer risk in chrt* studies in pstmenpausal wmen, but nt premenpausal wmen [171]. Based n a seven-day diary fr evaluating saturated fat intake, a high intake f saturated fat was reprted t increase the risk f breast cancer [166]. A meta-analysis* bserved a 19% increased risk f breast cancer with greater intake f saturated fats [172]. A prspective evaluatin cncluded that high ttal and saturated fat intake was assciated with a greater risk f ER+PR+ disease, but nt ER-PR- disease. High saturated fat was significantly assciated with greater risk f HER2- disease [162]. High-fat dairy intake, a significant surce f saturated fats, was psitively assciated with breast cancer recurrence, breast cancer mrtality, and verall mrtality [169]. N assciatin was bserved between lw-fat dairy and breast cancer. 0.5 t <1.0 dairy servings/day increased breast cancer mrtality by 20%. 1.0 dairy servings/day increased breast cancer mrtality by 49%. Other studies, hwever, have nt fund a significant assciatin between saturated fats and breast cancer [ ]. Trans-Fatty Acids Preliminary research indicates that these fatty acids may be assciated with an increased risk f cancer [170, ]. Minimal research exists n the relatinship between trans-fatty acids and risk f breast cancer, thus, mre research is needed fr cnclusive evidence. Hwever, evidence pints t a psitive assciatin between these fats and breast cancer risk [178, 180]. These fats may disrupt hrmnal systems that regulate healing, lead t the destructin f defective membranes, and encurage the develpment f cancer. 15

16 One study reprted a 40% increased risk f breast cancer in pstmenpausal wmen wh had higher tissue levels f trans-fatty acids [181]. Wmen wh cnsumed greater amunts f trans-fatty acids significantly increased their risk f breast cancer [179]. Wmen in the highest quintile f trans-fatty acid cnsumptin had a 75% increased risk cmpared with wmen in the lwest quintile. Pstdiagnstic trans fat intake was assciated with 45% and 78% increased risk f all-cause mrtality [170]. Omega-9 Fatty Acids (Mnunsaturated Fats) Mst research at this time indicates a neutral relatinship [173, 179] r a slightly prtective effect [175, ] between these fats and risk f breast cancer. Several case-cntrl* studies reprted that live il cnsumptin, rich in mega-9 fats, resulted in a 13-34% reductin in breast cancer risk [ ]. One study fund that wmen wh cnsumed 8.8 g/day f live il had a 73% lwer risk f breast cancer [184]. Oleic acid, an mega-9 fatty acid fund in live il, has been bserved t synergistically enhance the efficacy f trastuzumab (Herceptin) [189, 190]. A meta-analysis*, hwever, that included three chrt* studies reprted ttal mnunsaturated fatty acids and leic acid, t significantly increase breast cancer risk [171]. That said, in a meta-analysis f 13,800 patients, it was fund that the highest categry f live il cnsumptin was assciated with lwer dds f having any type f cancer [191]. These results were further supprted by this meta-analysis shwing thse with the greatest cnsumptin f live il having a 48% lwer risk f breast cancer cmpared with the lwest intake [192]. A prspective study, hwever, fund n relatinship between live il and breast cancer risk [193]. Plyunsaturated fats have a clear stimulating influence n mammary carcingenesis, whereas extravirgin live il diets mainly have a negative mdulatry effect n breast cancer develpment [194]. Oleurpein, the main live il plyphenl, has anti-prliferative effects. It was fund that treatment f breast cancer cells with leurpein culd help in preventin f breast cancer metastasis [195]. Olive il induces apptsis in sme cancer cells due t phenlic cmpunds like leurpein [196]. Essential Fatty Acids (EFA) Essential fatty acids are necessary fr the frmatin f healthy cell membranes, the prper develpment and functining f the brain and nervus system, and fr the prductin f hrmnelike substances called eicsanids* (thrmbxanes, leuktrienes, prstaglandins). Amng ther bdy functins, these chemicals regulate immune and inflammatry respnses. Eicsanids* frmed frm the mega-6 fatty acids have the ptential t increase bld pressure, inflammatin, platelet aggregatin, allergic reactins and cell prliferatin. Thse frmed frm the mega-3 fatty acids have ppsing affects. Current research suggests that the levels f essential fatty acids and the balance between them may play a critical rle in the preventin and treatment f cancer. 16

17 Omega-3 Fatty Acids Research is grwing supprting a prtective relatinship between mega-3 fatty acids [alpha linlenic acid (ALA), eicsapentanic acid (EPA), and dcsahexanic acid (DHA)] against the risk f breast cancer [ , 173, , ]. Studies shw that mega-3 fatty acids inhibit breast cancer tumr grwth and metastasis. Additinally, these fats are immune enhancing. Mechanisms prpsed fr their prtective effects include: Suppressin f eicsanid synthesis frm arachidnic acid (mega-6 fatty acid), which impedes immune functin [198, ]. Inhibit cell grwth and differentiatin via effects n gene expressin and signal transductin pathways [198, 203]. Alter estrgen metablism, which reduces estrgen-stimulated cell grwth [198, 203, 205]. Effects n insulin* sensitivity and membrane fluidity [203]. Anti-prliferative effects in breast cancer cells [206]. Inhibit prliferatin and induce apptsis [201]. A prspective study reprted that wmen wh cnsumed 44 g r mre f dietary marine surces f mega-3 fatty acids ver a 12 mnth perid reduced their risk f breast cancer by 26% when cmpared with wmen wh cnsumed 25 g r less [173]. Wmen with the greatest EPA, DHA, and ttal mega-3 fatty acids in their red bld cell membranes frm fish had a 73%, 94%, and 89% lwer risk f breast cancer, respectively [199]. In a prspective chrt* study, wmen with a lwer intake f marine-derived mega-3 fatty acids and a higher intake f mega-6 fatty acids had a significantly higher risk fr breast cancer; the researchers suggested that the balance between mega-6 and mega-3 fats may be f greater imprtance than the amunts f specific fatty acids [207]. High intake f fatty fish (mre than g f EPA and g f DHA) was assciated with a significantly reduced risk fr breast cancer in bth pre- and pstmenpausal wmen [208]. An inverse relatinship was fund between mega-3 fatty acids in breast tissue and the risk f breast cancer [190]. When cmparing wmen in the highest tertile f ALA and DHA t the lwest tertile, cancer risk was reduced by 61% and 69%, respectively. While n verall effect was bserved between mega-3 fatty acids and risk f breast cancer, mega-3 fatty acid intake significantly decreased the risk f breast cancer in bese wmen [209]. In a multivariate analysis f Greek wmen, elevated ttal plyunsaturated fatty acids in breast adipse tissue and mega-3 in buttck adipse tissue were assciated with reduced risk f breast cancer [210]. Mderate intake f fats (saturated fatty acids, mega-3 fatty acids, and mega-6 fatty acids) frm freshwater fish may decrease the risk f breast cancer amng premenpausal wmen [211]. Interestingly, the type f fish had varying effects with black carp (>500 g/m) and silver carp (>1000 g/m) significantly reducing risk while crutian carp (>1000 g/m) increased breast cancer risk. 17

18 Preliminary research indicates that DHA may synergistically enhance taxane cyttxicity [212]. Mre research is needed, but these findings wuld indicate that DHA during taxane administratin may imprve the effects f chemtherapy fr breast cancer patients. Fish and plant-based fds, hwever, cntain different types f mega-3 fatty acids. Fish cntains EPA and DHA, tw specific fatty acids that have shwn prmising results in the research literature [188, 199, 208, ]. Fish cnsumptin in general has been assciated with a prtective effect against breast cancer [189, 197, 199, 208, 213, 215]. The plant-based mega-3 fatty acid surces, such as flaxseed and thers listed in the table belw, cntain ALA. In an ideal envirnment, ALA is cnverted t EPA and DHA, hwever, this prcess is inefficient [102, 203, 216]. On the psitive side, the cnversin prcess is enhanced by fllwing a diet that is lw in saturated fats and lw in mega-6 fatty acids [203, 217]. Research suggests that higher intake f mega-3 fatty acid is related t decreased inflammatin and decreased physical aspects f fatigue amng breast cancer survivrs [218]. Survivrs with a high CRP, a marker f systemic inflammatin, had 1.8 times greater dds f fatigue. Omega-3 fat intake suggested an inverse assciatin with all-cause mrtality [170]. Fish il may ffset negative effects f armatase inhibitrs (AI) t bne; 4 g EPA and DHA daily fr 3 mnths reduced bne resrptin in breast cancer survivrs [219]. In a randmized duble blind placeb cntrlled trial, 70% f patients wh tk an mega-3 supplement during chemtherapy did nt develp peripheral neurpathy cmpared with 40.7% in the placeb grup [220]. Omega-6 Fatty Acids Recent studies indicate that a high intake f mega-6 fatty acids (linleic acid, which can be cnverted t arachidnic acid) prmte breast tumr develpment and metastasis [167, 190, 197, ]. A meta-analysis* f 3 chrt* studies fund palmitic acid, a type f mega-6 fatty acid, t be significantly assciated with an increased risk f breast cancer [171]. Additinally, researchers reprted that arachidnic acid, an mega-6 fatty acid almst exclusively frm meat, significantly increased xidative damage as measured by urinary bimarkers [222]. It is knwn that cyclxygenase is the rate-limiting enzyme that catalyzes the cnversin f arachidnic acid t prstaglandins. Furthermre, COX-2 is knwn t be verexpressed in varius human cancers. In this breast cancer study, COX-2 verexpressin was significantly crrelated with larger tumr size and advanced clinical stage, which indicates a prer prgnsis [221]. A very interesting finding was reprted in a prspective study that fund n verall assciatin between mega-6 fatty acids and risk f breast cancer [173]. Hwever, mega-6 fat cnsumptin increased risk by 87% in wmen wh cnsumed 25 g r less f marine mega-3 fatty acids. This effect was even greater fr advanced breast cancer. Thus, the balance between mega-6 and mega-3 fatty acids may be f paramunt imprtance. This was further supprted by ther studies [190, 197, ]. In this study, higher intake f mega-6 fatty acids t mega-3 fatty acids was assciated with significantly higher CRP values and these patients were significantly mre likely t experience fatigue [218]. 18

19 Fat Bttm Line Aim fr lw t mderate fat; fcus n type and quality. Nte that all fats are equally high in calries. Limit animal fats. Avid hydrgenated fats. Fcus n extra-virgin live il, avcads, and nuts/seeds as healthy fat surces. Increase mega-3 fatty acids. Fatty Acid Dietary Surces Recmmendatin Saturated fatty acids Meats, pultry skin, baked gds, ccnut il, and whle milk dairy prducts, including butter, cheese, and ice cream Reduce r eliminate meat and whle milk dairy prducts. Trans fatty acids Omega-9 fatty acids Omega-3 fatty acids: EPA and DHA ALA Margarine, fried fds, cmmercial peanut butter, salad dressings and varius prcessed fds including breads, crackers, cereals, and ckies Extra-virgin live il, almnd il, canla il, macadamia nut il, almnds, and avcads Cld-water fish (fr example: salmn, sardines, black cd, trut, herring), and DHAenriched eggs Flaxseeds, chia seeds, walnuts, hempseeds, and pumpkin seeds Avid trans r hydrgenated fats. Prducts may be labeled trans fat free if they cntain less than 0.5 mg per serving. Include these healthy fats daily. Limit cnsumptin f nuts t n mre than ¼ cup with meal r snack t limit ttal fat and calries. Include these healthy fats daily thrugh diet and/r supplements. It may be wise t cnsume cld water fish r fish il supplements at least twice weekly t btain an adequate amunt f EPA and DHA. Omega-6 fatty acids: Arachidnic acid Linleic acid Meats, butter, egg ylks, whle milk, and whle milk dairy prducts Cmmn vegetable ils, such as crn il, safflwer il, sunflwer il, and cttnseed il, and prcessed fds made with these ils 19 If yu chse t use a supplement, pt fr ne that is highest in EPA and DHA cncentratin. Reduce r eliminate meat and whle milk dairy prducts. Limit cnsumptin f linleic acid-rich ils. Substitute an mega-9 fatty acid-rich il fr yur current cking il r fat.

20 Meat Animal fat [26, 161, 225] and meat appear t increase the risk f breast cancer in recent studies [16, 168]. Cnversely, plant fat has been negatively assciated with breast cancer [225]. In a study f ver 35,000 wmen, meat cnsumptin significantly increased the risk f breast cancer in bth premenpausal and pstmenpausal wmen [226]. Wmen eating 1.75 z f prcessed meat daily increased the risk f breast cancer by 64% in pstmenpausal wmen cmpared t wmen wh did nt eat meat. Cnsumptin f red and fried meat quadrupled the risk f breast cancer in a case-cntrl study in Brazil [14]. Meat cnsumptin increased the risk f breast cancer risk by 56% fr each additinal 100 g (3.5 z) daily f meat cnsumptin in a French case-cntrl study [190]. Regular cnsumptin f fatty red meat and prk fat increased the risk f breast cancer by 348% and 632%, respectively in a small Brazilian study [227]. A large case-cntrl* study fund that wmen wh cnsumed very well-dne meat fr hamburger, bacn, r steak had a 54%, 64%, and 221% increased risk fr breast cancer, respectively [228]. Frequent cnsumers f these well-dne meats had a 462% greater risk f breast cancer. High intake f red meat is assciated with a significantly higher breast cancer risk, especially fr well-dne red meat [229]. This is slightly strnger fr pstmenpausal wmen than premenpausal wmen. Fd Categry Summary Recmmendatin Fruits and vegetables One serving = ½ cup fruit r vegetable 1 cup raw leafy greens ¼ cup dried fruit r vegetable 6 z fruit r vegetable juice At least 5, preferably 8-10 ttal servings daily [230] 5 r mre vegetable servings 3 fruit servings Fiber Eat 1 cup r mre vegetables with lunch and dinner. Chse breads with 3 r mre grams f fiber per slice. First ingredient n the label shuld be whle r spruted grain flur, nt white flur, unbleached white flur, r enriched wheat flur. Whle grains include ats, barley, brwn rice, quina, amaranth, bulgur, millet, buckwheat, spelt, wild rice, whle wheat, and teff grams daily This gal can be achieved by meeting yur fruit and vegetable gal plus ne serving f chia/ flax seeds r ne serving f legumes r at least tw servings f whle grains. 20

21 Refined carbhydrates and sugars Meat Dietary surces include prducts made with refined flurs (fr example: white bread, white rice, white pasta) r refined grains, alchl, sdas, drinks cntaining added sugars, and desserts, such as candy, ckies, cakes, and pastries. Dietary surces include beef, prk, and lamb. Prcessed meats include deli meats, bacn, sausages, and ht dgs. Limit r avid cnsumptin. Reduce r eliminate meat cnsumptin. Avid prcessed, grilled r fried meats. GENOTOXINS: Hetercyclic Amines (HCAs) & Plycyclic Armatic Hydrcarbns (PAHs) Natural cmpnents in meat, such as amin acids, creatine*, and plysaccharide precursrs, are cnverted t HCAs during high-temperature cking. HCAs are knwn t cause cancer in labratry animals [ ]. While human research is frthcming, the majrity f studies [228, ], althugh nt all [ ] have bserved a significant assciatin between HCAs and breast cancer. PhIP, ne f the mst abundant HCAs frm cked meat has ptent estrgenic effects [233]. Researchers have therized that the estrgenic prperties f PhIP influence metastatic ptential. Daily intake f smked meats mre than dubled the risk fr breast cancer in bth pre- and pstmenpausal wmen; this risk mre than tripled in wmen wh carried the SULTA1A1 gentype [236]. Carcingenic activity f HCA s is affected by varius dietary factrs [239]: Factrs that enhance carcingenesis* when cmbined with HCAs include: High-fat diet Caffeine Factrs that inhibit carcingenesis* when cmbined with HCAs include: DHA Cnjugated linleic acid (CLA) Isflavnes Diallyl Sulfides (fund in the allium family, such as garlic, nins, leaks, and shallts) Green tea catechins* [240] Indle-3 carbinl Prbitics 21

22 Gamma-tcpherl The mst imprtant variables cntributing t the frmatin f HCAs are: Cking temperature (greater than 300 F) Cking time (greater than 2 minutes) Cking methd (frying, ven grilling/briling, barbecuing) Charring f fd (charcal-briled r smked fds) cntribute t PAHs [241]. Meat can ptentially be made safer t eat by being cked in a way that des nt lead t HCA frmatin. Chse lean, well-trimmed meats t grill. Using marinades significantly reduces the amunt f HCAs. Brief micrwave preheating substantially reduces HCA cntent f cked meat. Small prtins require less time n the grill. Additinally, the type f prtein cked can als affect the cncentratin f HCAs. It has been reprted, fr example, that chicken has mre than 100 times the number f HCAs than salmn [239]. Lndn briled steak had mre than 600 times the amunt f HCAs when cmpared t salmn. Grill vegetables r meat alternatives that d nt lead t the frmatin f HCAs r PAHs. Research suggests that ur genetics may als influence risk. Cnsumptin f well-dne meat increased breast cancer risk 8-fld fr pstmenpausal wmen wh carried the NAT2 gentype, cmpared t thse wh cnsume medium-dne r rare meats [242]. Daily intake f smked meat was significantly assciated with a greater verall breast cancer risk fr thse with the SULT1A1 gentype, in bth pre- and pst-menpausal wmen [236, 243]. ALCOHOL Regular cnsumptin f alchl may increase the risk fr breast cancer [ ]. A recent review study reprted that data frm many well-designed studies cnsistently shws a small rise in breast cancer risk with increasing cnsumptin f alchl [249]. A recent study fund that as little as a half a glass f wine a day raised a wman s risk f develping breast cancer by 6% (increased risk by 18% in pstmenpausal wmen) [244]. Furthermre, 1-2 drinks a day increased risk by 21% and 2 r mre drinks a day increased risk by 37%. The heightened risk was mre prnunced fr wmen with ER+ and PR+ tumr types. Cnsuming as little as 3-6 drinks/week was assciated with increased breast cancer risk, and wmen wh had at least 2 drinks daily n average had a 51% greater risk f breast cancer cmpared t thse wh never cnsumed alchl [255]. 22

23 Wmen wh drank tw r mre alchlic drinks daily in the five years prir t diagnsis had an 82% increased risk f breast cancer cmpared t nn drinkers [250]. A pled analysis f six prspective studies suggests that the risk f breast cancer increases linearly by 9% with each 10 g/day (~1 drink) alchl [256]. The risk increased t 41% when cmparing wmen wh cnsumed g/day (~2-5 drinks) t nndrinkers. A large meta-analysis* revealed that ne drink daily increased breast cancer risk by 11% [257]. A later meta-analysis* fund similar findings [258]. Since then, anther meta-analysis* reprted that breast cancer risk increased by 32% and 46% in wmen wh cnsumed g alchl (~3-4 drinks) daily and 45 g r mre (~4.5 drinks r mre) daily, respectively [247]. Fr each additinal 10 g f alchl (~1 drink) daily, risk increased by 7%. Other studies claim that ne glass f alchl daily des nt increase risk, but cnsuming 2-5 drinks daily increases the risk f breast cancer by 40% cmpared t nn-drinkers [245]. Greatest risk was amng heavy drinkers wh were als pstmenpausal and had a histry f benign breast disease r wh used hrmne replacement therapy (HRT). Similarly, a French study fund that drinking g wine (~ drinks) daily lwered the risk f breast cancer, but when intake increased abve 12 g daily, the risk f breast cancer increased [259]. Alchl cnsumptin between menarche and first pregnancy was assciated with a greater risk f breast cancer; this risk increased with lnger menarche t pregnancy intervals [260]. Amng ER+ pstmenpausal wmen, thse wh cnsumed apprximately 3 drinks r mre daily had a 76% increased risk f breast cancer when cmpared with wmen wh did nt cnsume alchl [261]. The assciatin between alchl and ER- tumrs was less clearly assciated. Additinally, there was n clear assciatin between alchl and premenpausal risk f breast cancer. A recent chrt* study f pstmenpausal wmen reprted that alchl cnsumptin was assciated with an increased risk f breast cancer in ER+, but nt ER- tumrs [262]. On a similar nte, a recent meta-analysis* reprted that an increase in 10 g (~1 drink) alchl daily increased the risk f breast cancer, especially fr wmen with ER+ breast cancers ER+ (12% risk), all ER- (7% risk), ER+PR+ (11% risk) ER+PR- (15% risk), ER-PR- (n effect) [251]. Petri and clleagues [248] bserved a strnger relatinship between alchl and breast cancer in pstmenpausal wmen cmpared t premenpausal wmen. Premenpausal wmen drinking mre than 27 drinks per week had a 3.5% higher risk than wmen wh had ne drink per week. Pstmenpausal wmen drinking six r mre alchlic beverages per week had a 2.4% higher risk than wmen wh had ne drink per week. On the cntrary, wmen wh drank abut 1.5 drinks per week had a 40% greater likelihd f develping breast cancer cmpared t nn drinkers and this was mst prnunced in wmen wh were premenpausal at diagnsis [252]. 23

24 Alchl cnsumptin (1 drink/day) during a wman s fifties increased risk fr pstmenpausal breast cancer by 12% in a large chrt* study, but statistical significance was nt reached fr wmen in their twenties, thirties, r frties [246]. These differing findings between pre- and pstmenpausal wmen are likely related t the effect f alchl n estrgen levels. Alchl appears t increase endgenus* estrgen levels [ ]. Anther thery is that alchl cnsumptin culd metablically cnvert "lw-risk" breast cancer patients t "high-risk" status via xidative mitchndrial metablism by fueling tumr cell grwth [268]. Antixidants such as N-acetyl cysteine (NAC) can effectively reverse r prevent ethanlinduced xidative stress in cancer-assciated fibrblasts. Flate, a B vitamin, may be f even greater significance with alchl cnsumptin. It has been bserved that wmen with lw flate and high alchl cnsumptin had a 43% greater risk f breast cancer when cmpared with nndrinkers with adequate flate intake [269]. Alchl Bttm Line It is best t limit r avid alchl. ADEQUATE FLUIDS The functins f water in the bdy include the fllwing: Carries nutrients and waste prducts. Participates in chemical reactins. Acts as a lubricant and cushin arund jints. Acts as a shck absrber in the eyes and spinal crd. Aids in the bdy s temperature regulatin. Maintains bld vlume. Increased fluid intake is needed fr a high fiber diet. Drink plenty f water daily t help meet fluid needs. CALORIC INTAKE The risk f breast cancer is much higher in industrial cuntries than in develping cuntries where wmen are characterized by lwer energy intake and higher energy expenditure. Mdest calric restrictin has been shwn t inhibit tumr grwth in animal mdels decrease xidative DNA damage [270]. Mdest calric restrictin has been shwn t decrease xidative DNA damage. The mechanism invlved may be related t the decrease in IGF-I bserved when calric intake is restricted [ ]. Furthermre, evidence suggests that a high calrie diet may increase IGF-I levels [273]. 24

25 BODY MASS Wmen with a BMI f 25 kg/m 2 had a 58% increased risk f breast cancer [7]. Epidemilgic evidence suggests a psitive assciatin between bdy mass and pstmenpausal breast cancer in many [ ], but nt all studies [ ]. Increasing BMI was assciated with a 40% increased incidence and mrtality f breast cancer in pstmenpausal wmen [285]. Similarly, a high BMI (>27 kg/m 2 ) increased breast cancer mrtality in ER+PR+ wmen [224]. Wmen with a BMI f 25 kg/m 2 had a 58% increased risk f breast cancer [7]. Obese pstmenpausal wmen had 3.26-fld increased risk fr breast cancer cmpared t healthy weight wmen [286]. In wmen with breast cancer, height and BMI were assciated with pstmenpausal breast cancer [287]. This effect was mst prnunced in wmen with ER+ tumrs. Obese pstmenpausal wmen had a 50% increased risk fr breast cancer [277]. BMI was psitively assciated with risks f ER+ and triple-negative breast cancer in wmen ages 50 t 84 wh were nt users f hrmne therapy [279]. Increasing BMI was assciated with a 40% greater incidence and mrtality f breast cancer in pstmenpausal wmen [285]. A case-cntrl* study f 2,000 wmen fund that wmen wh gain weight, particularly after age 50, significantly increase their risk f breast cancer [288]. Cnversely, wmen (yung and middle-aged) wh lse weight may decrease the risk f breast cancer. This study suggests excess bdy fat increases estrgen levels, which may in turn increase the risk fr breast cancer. An earlier study reprted similar findings with ttal weight gain serving as a strng predictr f breast cancer risk, specifically amng frmer and never HRT users [274]. Weight gain thrughut adulthd is assciated with an increased risk f breast cancer in Chinese wmen [289]. High recent BMI was assciated with increased risk f ER- and PR+ tumrs amng pstmenpausal African-American wmen [282]. Results frm a systematic review shwed that, when adjusted fr BMI, a larger waist size increased risk f breast cancer amng premenpausal wmen [290]. This study supprts the idea that central besity is f greater cncern than general besity in regards t breast cancer risk. Hwever, fr pstmenpausal wmen, a large trial fund that, while general besity was a significant predictr f breast cancer risk, central besity did nt appear t be assciated with increased risk [291]. Ttal bdy weight, BMI, and hip circumference were significantly assciated with breast cancer risk amng HRT nnusers; bese wmen (BMI >30 kg/m²) had a 31% greater risk cmpared t wmen with BMI <25 kg/m² [291]. 25

26 Premenpausal wmen with a BMI f 25.0 kg/m² shwed a tendency twards ER- tumrs when cmpared t premenpausal wmen with a BMI f <25.0 kg/m² [292]. Data frm tw large preventin trials suggests that higher levels f BMI were significantly assciated with increased breast cancer risk in premenpausal wmen lder than 35 years, but nt pstmenpausal wmen [284]. Hwever, results f a meta-analysis* using 50 studies fund n significant crrelatin between BMI and premenpausal breast cancer risk [280]. Tw studies reprted that BMI was significantly assciated with a larger-tumr size at diagnsis and a higher prbability f having psitive axillary lymph ndes [283, 293]. Overweight r besity is assciated with prer prgnsis in the majrity f the studies that have examined bdy mass and breast cancer [151, ]. Many studies [151, ], thugh nt all [306], reprt increased BMI r bdy weight t be a significant risk factr fr recurrent disease, survival, r bth. It has been suggested that the assciatin f besity with prer utcmes after breast cancer bserved in previus studies may be driven predminantly by the relatinship between mrbid besity ( 40 kg/m²) and mrtality. Hwever in ne study, wmen with a 24.0 kg/m² BMI had increased risk f lcreginal recurrence [307]. High BMI and breast cancer may be related due t increased estrgen [277, ] and elevated insulin* [310] and IGF, which can stimulate cell prliferatin [140, 308]. Obese pstmenpausal wmen (BMI >30 kg/m²) had 35% higher cncentratins f estrne* and 130% higher cncentratins f estradil* cmpared with lighter-weight wmen (BMI <22.0 kg/m²) [294]. Additinally, free estradil* and free teststerne were tw t three times greater in verweight and bese wmen cmpared with lighter-weight wmen. Armatase inhibitrs may be less effective at lwering estradil values in bese wmen [311]. Similarly, while nrmal weight patients wh used anastrzle fr an additinal 3 years halved their risk f disease recurrence and death and had nly a fifth f the risk f distant metastases, verweight and bese patients derived n benefit frm an additinal 3 years f anastrzle [302]. On the ther hand, anther study fund that BMI may nt influence utcmes fr wmen with hrmne receptr-psitive breast cancer using armatase inhibitrs [312]. Recent findings indicated that xidative damage, measured by urinary bimarkers, was significantly greater in wmen with a higher BMI [222]. Obesity amng premenpausal wmen, hwever, may nt be assciated with increased risk f breast cancer. Nnetheless, besity during menstruating years is assciated with besity thrughut life and therefre t an eventual increased risk f breast cancer [185]. Hwever, ther research suggests a strnger relatinship between bdy weight and breast cancer in premenpausal wmen [298, 300]. A chrt* study f 1,300 wmen reprted that breast cancer recurrence and death increased with bdy weight in bth premenpausal and pstmenpausal wmen [232]. In a chrt* study with mre than 1,100 wmen, a BMI ( 23.0 kg/m²) was independently assciated with pr prgnsis in hrmne receptr-psitive breast cancer [305]. BMI 25.8 kg/m² was assciated with breast cancer-specific death and BMI <21.2 kg/m² was assciated with all-cause and breast cancer-specific death amng patients with ER + r PR + tumrs [281]. 26

27 Obesity was assciated with prer survival in wmen with nde-psitive breast cancer [301, 304] and in yunger wmen [304]. Hwever, n significant relatinship was bserved between besity and recurrence-free survival r verall survival in patients with triple negative breast cancer [ ]. BMI may nt influence survival fr wmen with metastatic breast cancer [315]. Bdy weight prir t breast cancer diagnsis significantly increased risk f recurrence and death in nnsmkers [298]. Additinally, nnsmkers wh gained weight after diagnsis had an elevated risk f breast cancer death during fllw-up (median, 9 years), cmpared with wmen wh maintained their weight. Research suggests a ptential link between besity, diabetes mellitus and breast cancer [316]. Eating fds high in vitamin C, such as fruits and vegetables, may prvide a prtective effect frm breast cancer fr verweight wmen (BMI>25 kg/m²) [317]. Additinally, breast cancer survivrs whse BMI was 30 kg/m² at the time f breast cancer treatment were apprximately 3.6 times mre likely t develp lymphedema at 6 mnths after diagnsis than thse with a BMI < 30 kg/m² at the time f cancer treatment [318]. PHYSICAL ACTIVITY Lw levels f physical exercise appear t be assciated with the risk f breast cancer [249, 276, ]. Similarly, physical activity seems t reduce the risk f breast cancer [ ]. In a chrt* study f ver 50,000 wmen, the effect was strngest in pstmenpausal wmen ER+, PR+ disease [331]. A large review f 73 studies fund that breast cancer risk was reduced by 25% amngst physically active wmen as cmpared t the least active wmen [327]. The EPIC study reprted that amng wmen diagnsed with breast cancer after age 50, the largest risk reductin was fund with highest activity, whereas fr cancers diagnsed befre age 50 strngest assciatins were fund fr mderate ttal physical activity [329]. African American wmen wh engaged in vigrus physical activity ( 2 hurs/week in the past year) had a 64% reduced risk f breast cancer cmpared t thse wh did nt participate in any vigrus activity [330]. Hwever, in ne study, greater physical activity was assciated with reduced breast cancer risk amng White wmen nly; this study nly assessed ttal activity nt intensity [322]. Lifetime ttal physical activity has been assciated with a decreased risk f breast cancer [ ] and breast cancer-specific mrtality [ ]. Sme studies indicate that physical activity has a mre significant effect in reducing risk f breast cancer in pstmenpausal wmen [338]. Exercise between the years f appears t be the mst beneficial in reducing risk f breast cancer [332]. While physical activity did nt decrease breast cancer risk fr wmen wh were lng-term users f HRT, risk did decline fr wmen wh did nt use HRT, wh used HRT fr <5 years, r wh were currently using estrgen alne [335]. 27

28 A case-cntrl* study reprted significantly reduced breast cancer risk amng wmen wh maintained, n average, 17.6 MET-h/week 2 frm menarche nward [276]. This decreased risk with physical activity was limited t wmen withut a family histry f breast cancer when adjusted fr BMI. Pst-menpausal wmen wh exercised the equivalent t running fr 3 hurs weekly and thse that were active t the equivalent f 24 hurs weekly f mderate husehld wrk reduced breast cancer risk by 40% [339]. A chrt* study f ver 73,000 wmen reprted that the mst active wmen (thse reprting >42 MET-h/week) 3 experienced a 25% lwer risk f breast cancer than the least active wmen [325]. 47% f wmen reprted walking as their nly recreatinal activity; amng these wmen, a 14% lwer risk was bserved fr 7 hurs/week relative t 3 hurs/week f walking. A chrt* study reprted that pstmenpausal wmen wh were mst physically active (>42.0 MET-h/week)3 at baseline had a 29% lwer incidence f breast cancer than active wmen with the least activity (>0-7.0 MET-h/week) 4 [321]. This difference was greatest fr wmen wh did nt use HRT at enrllment. Wmen wh engaged in regular strenuus physical activity at age 35 had a 14% reduced risk f breast cancer cmpared with less active wmen [320]. A similar trend was bserved fr regular strenuus activity at age 18 and at age 50. These findings were cnsistent with wmen wh did and did nt use HRT. Furthermre, a prspective bservatinal study reprted that physical activity after a breast cancer diagnsis may reduce the risk f death frm this disease [319]. The greatest benefit ccurred in wmen wh perfrmed the equivalent f walking 3 t 5 hurs per week at an average pace. The benefit f physical activity was particularly apparent amng wmen with hrmne-respnsive tumrs. As nted earlier, the cmbinatin f cnsuming five r mre daily servings f vegetables and fruits, and accumulating 540+ metablic equivalent tasks-min/wk (equivalent t walking 30 minutes 6 d/ wk) decreased mrtality by nearly 50% [13]. The effect was strnger in wmen wh had ER+ cancers. While ttal physical activity had a strnger inverse relatinship fr ER+/PR+ breast tumrs, husehld physical activity was inversely assciated with ER-/PR- tumrs [329]. Increased physical activity fllwing breast cancer diagnsis significantly decreased the risk f dying frm breast cancer and imprved verall survival when cmpared with wmen wh exercised <2.8 MET-h/wk [340]. A lwer risk f all-cause death was bserved fr wmen wh engaged in an average f 9 MET-h/ wk (~3 h/wk f fast walking) f recreatinal physical activity frm menarche t diagnsis cmpared with wmen wh did nt exercise [337]. A meta-analysis* f chrt* studies reprted that bth prediagnsis and pstdiagnsis physical activity were assciated with reduced breast cancer-specific mrtality and all-cause mrtality [341]. Findings frm a randmized cntrlled trial suggested that thse wh were mst active at baseline had a 53% lwer mrtality risk cmpared t the least active wmen [342]. 2 This is equivalent t a 150 lb individual burning 1257 kcals/week thrugh physical activity. 3 This is equivalent t a 150 lb individual burning abut 3000 kcals/week thrugh physical activity. 4 This is equivalent t a 150 lb individual burning 500 kcals/week r less thrugh physical activity. 28

29 Pst-diagnsis running, a mre vigrus exercise, is assciated with significantly lwer breast cancer mrtality than pst-diagnsis walking [343]. Wmen participating in 9 MET-h/wk r mre (~3 h/wk f fast walking) f physical activity befre diagnsis had a lwer all-cause mrtality cmpared with inactive wmen [344]. Wmen participating in 9 r mre MET-h/wk f physical activity after diagnsis had lwer breast cancer mrtality and lwer all-cause mrtality. Survival may be enhanced by physical activity in thse wmen wh exercised the year prir t diagnsis, especially wmen wh were verweight r bese [345]. Physical activity can help ease cancer-related fatigue during and fllwing cancer treatment [228, 229, 348] and imprve quality f life amng survivrs [ ]. Survivrs that reprted greater weekly mderate vigrus physical activity als reprted less depressed md and lwer clinician-rated depressin [348]. A review f survivrship studies fund that mst reprts demnstrated that physical activity led t an imprved verall and breast cancer-specific survival [349]. This effect may even be greatest in lder wmen. Physical activity may reduce the risk f breast cancer thrugh an influence n varian functin and a decrease in prgesterne and estrgen cncentratins via reduced bdy fat [320]. Furthermre, exercise may increase sex hrmne-binding glbulin* (SHBG) levels and thereby reduce estradil*. An increase in lean bdy mass (ften achieved thrugh physical activity) was assciated with a favrable change in 2-hydrxyestrne: 16-a-hydrxyestrne, a prpsed bimarker f breast cancer risk [350]. Additinally, exercise reduces CRP levels [352], serum insulin* levels [ ], serum IGF-I levels [217,232], and imprves insulin* sensitivity [320, 352]. Mderate- t vigrus-intensity activity als assciated with a lwer fasting plasma glucse [352]. Greater physical activity in bese wmen was assciated with significantly less mammgraphic density, pssibly suggesting anther mechanism fr the prtective effect f physical activity [353]. Mderate-intensity exercise lwers the increased risk f breast cancer in diabetic wmen [354]. Healthy weight cntrl is encuraged with an emphasis n exercise t preserve r increase lean muscle mass. Additinal Nutritinal and Lifestyle Factrs fr Breast Cancer Survivrs ANTIOXIDANTS* Fund in abundance in fruits and vegetables! Prevent xidative damage in bdy cells. Research indicates a link between xidant damage and breast carcingenesis*. Examples f antixidant* nutrients and nn-nutrients include vitamins A, C, and E, selenium, lycpene, and beta-cartene. 29

30 While research generally supprts dietary antixidants mre s than supplemental antixidants*, a Canadian case-cntrl* study reprted that cmpared t n supplementatin, wmen wh tk vitamin C, E, beta-cartene, and zinc supplements fr 10 r mre years may be prtected frm develping breast cancer [355]. Nte that patients may be advised t NOT cnsume high-dse antixidant* supplements during chemtherapy r radiatin therapy. Antixidant* cnsumptin via fd surces and a basic multivitamin supplement are cnsidered safe. Selenium Antixidant* that scavenges free radicals and suppresses damage due t xidatin. Als is essential fr the immune system. Prmising evidence indicates that selenium may decrease the risk f breast cancer [ ]. Selenium inhibits cell prliferatin and induces apptsis* [ , 364]. Selenium may interfere and alter estrgen receptrs decreasing mammary tumr incidence [358]. In a Swedish chrt* study f ver 3,000 wmen diagnsed with breast cancer, dietary selenium intake was inversely assciated with breast cancer mrtality and verall mrtality [362]. Research shws that selenium reduces the incidence f malignant cells in animal mdels [359], and enhances the effects f chemtherapeutic drugs, such as [357] taxl and adriamycin [357, 361]. Tenail selenium cncentratins tended t be lwer in pstmenpausal breast cancer patients when cmpared with healthy nn-cancer patients, but the differences did nt reach statistical significance [365]. Interestingly, this study als fund that plasma triidthyrnine (T3) (a thyrid hrmne) cncentratin was psitively assciated with tenail selenium in breast cancer patients and cntrls. T3 cncentratin was significantly lwer in breast cancer patients cmpared t healthy nn-cancer patients. One study suggested the cmbinatin f selenium and idine, typical f a Japanese diet, act synergistically in decreasing breast cancer risk [366]. It is knwn that idine plays an imprtant rle in thyrid functin. Thus, selenium status may affect bth thyrid hrmne status and idine availability. Selenium is a precursr t the glutathine* (GSH) antixidant* system. GSH is the principal prtective mechanism f the cell and is a crucial factr in the develpment f the immune respnse by the immune cells [367]. Studies suggest the rati f selenium t glutathine* is lwer in breast cancer patients [356]. Research indicates that dietary selenium supplements crrect abnrmal glutathine* turnver. Additinally, the type f selenium may have influential effects. Selenium in the frm f selenmethinine r methylseleninic acid may reduce/delay breast cancer metastasis whereas sdium selenite appears t exacerbate cancer grwth [368]. 30

31 Turmeric (Curcumin) Curcumin, the yellw pigment and active cmpnent f turmeric and many curries, is a ptent antixidant*, that exhibits chempreventive and grwth inhibitry activity in several tumr cell lines [ ]. Tetrahydrcurcumin, ne f the majr metablites f curcumin, exhibits significant inhibitin f breast cancer cell grwth [376]. Curcumin and tamxifen synergistically inhibited cancer cells [373]. Nte that curcumin has been shwn t inhibit cyclphsphamide-induced apptsis*, thus it s advisable t nt use curcumin supplements when taking cyclphsphamide [377]. Evidence suggests that curcumin may suppress tumr initiatin, prmtin and metastasis [371, 378]. This may ccur thrugh enhanced apptsis* [369, 371]. Additinally, curcumin prmtes detxificatin in the liver and pssesses anti-inflammatry activity, pssibly by inhibiting COX-2 activity [ ]. Curcumin prlnged tumr-free survival in mice [375]. Vitamin C Studies assessing vitamin C and the risk f breast cancer are mixed abut half f the studies supprt vitamin C t be prtective [9, 36, ] while the ther half suggest n assciatin [ ]. Vitamin C induces appttic effects n breast cancer cells [382]. Lw plasma levels f vitamin C have been assciated with a greater risk f breast cancer [391]. Dietary vitamin C has been significantly assciated with reduced mrtality in breast cancer survivrs [36]. Furthermre, risk f recurrence and mrtality was reduced in wmen wh cnsumed vitamin C supplements fr mre than three years [392]. Wmen in the highest quartile f pre-diagnsis vitamin C intake had a 25% lwer risk f breast cancer mrtality cmpared with thse in the lwest quartile yet n assciatin was fund between pst-diagnsis vitamin C supplement use and mrtality frm breast cancer [393]. A meta-analysis* examining vitamin C intake and breast-cancer specific mrtality cncluded that pst-diagnsis vitamin C supplementatin may be assciated with a reduced risk f mrtality [383]. In a study f 45 patients with varius cancers, g f vitamin C were administered after standard chemtherapy treatments; high dse intravenus vitamin C lead t lwer CRP values, a bimarker fr inflammatin [394]. A randmized 5-mnth study f breast cancer patients underging chemtherapy shwed that c-administratin f vitamins C (500 mg daily) and E (400 IU daily) restred their antixidant* status, reduced DNA damage, and may be useful in prtecting against chemtherapy related side-effects [395]. 31

32 Vitamin E Vitamin E acts as a cellular antixidant* and an anti-prliferating agent. It cnsists f bth tcpherls and tctrienls. Sme research indicates that tctrienls are the cmpnents f vitamin E respnsible fr grwth inhibitin in human breast cancer cells [396]. Research is incnsistent n the prtective effects f vitamin E and breast cancer. Data frm mst prspective studies have nt revealed a prtective relatinship between vitamin E and risk f breast cancer [384]. While supplemental vitamin E des nt cnsistently appear t ffer prtectin against breast cancer [222], taking vitamin E fr mre than three years has been assciated with a mdest prtective effect [392]. Additinally, these researchers reprted a decreased risk f recurrence and mrtality assciated with lng-term use f vitamin E supplements. The Shanghai Breast Cancer study was a ppulatin based case-cntrl* study that fund a 20% reductin in breast cancer risk with vitamin E supplementatin [397]. Additinally, lw plasma levels f vitamin E have been assciated with a greater risk f breast cancer [391]. It was demnstrated recently that dietary vitamin E, unlike supplemental surces f vitamin E, significantly reduced xidative damage as measured by urinary bimarkers [222]. Nte that findings suggest that vitamin E supplements (400 mg) may interfere with the therapeutic effects f tamxifen [398]. Resveratrl Resveratrl is a plyphenl* fund primarily in red grape skins with knwn antixidant and antiinflammatry prperties, and is emerging as a ptent chempreventive and anticancer drug [399]. Resveratrl has exhibited ptential anticarcingenic activities in several studies. Reduced tumr grwth, decreased angigenesis, and induced apptsis in mice [400]. Less tumrs and lnger tumr latency in a rat study [401]. May inhibit IGF-I mediated cell migratin in breast cancer cells [402]. Induces apptsis in breast cancer cells [ , 403]. Decreased levels f vascular endthelial grwth factr (VEGF) in breast cancer cells [400]. Inhibited cell grwth and regulates IGF-II in breast cancer cells [404]. Lessened DNA damage [403]. Recent evidence indicates that resveratrl and glucans have significant synergistic effects n immune functin [405]. Even at lw cncentratins, phytestrgens such as resveratrl have anti-prliferative effects n breast cancer cells in an ER-dependent manner. At the same time, they als have the capability f maintaining nrmal breast cell survival via an ER-independent mechanism [406]. 32

33 Nutrient/Phytnutrient Summary Recmmendatin Selenium Dietary surces include Brazil nuts, seafd, enriched brewer s yeast, and grains. Turmeric (curcumin) Vitamin C Vitamin E Resveratrl Selenium cntent depends smewhat n the amunt f selenium in the sil in which the prducts are grwn. A deep range-yellw spice cmmnly used in curries and Indian cuisine. Dietary surces include varius fruits and vegetables, including papaya, citrus fruits, kiwi, cantalupe, mang, strawberries, bell peppers, brccli, and tmates. Dietary surces include vegetable ils, wheat germ, sweet ptates, nuts, seeds, and avcads. Dietary surces include grapes, grape prducts, peanuts, sy, mulberries, and cranberries. 200 mcg selenium daily thrugh diet and/r supplements Tw Brazil nuts prvide 200 mcg selenium. Eat liberally. Include these fruits and vegetables daily. Eat vitamin E-rich fds regularly. Mre research is needed t assess whether r nt supplements wuld be beneficial. Eat resveratrl-rich fds regularly. Mre research is needed t assess whether r nt supplements wuld be beneficial. Flax Flax may wrk t blck tumr grwth, inhibit angigenesis*, and enhance the immune system [407]. Cnsumptin f 5 r 10 g flax fr 7 weeks significantly decreased bld levels f estrne* and estradil* [408]. Flax has been shwn t enhance the effects f tamxifen [409]. Flaxseed is the greatest surce f mammalian lignans* [ ], phytestrgens fund in flax, which appear t bind with estrgen and lwer circulating levels f estrgen. This actin may act as ne f the prtective mechanisms f flax against breast cancer. Lignans* facilitate the remval f estrgens via increased retentin within the gut, which are later eliminated in the feces [ ]. Furthermre, lignans* psitively influence estrgen metablism by imprving the rati f 2:16a hydrxyestrne [ ]. 33

34 Lignans appear t mdulate the develpment f breast cancer cells and significantly inhibit cell grwth [414]. In ne study, flaxseed (25 g daily) and its metablites, such as lignans*, reduced tumr grwth in patients with breast cancer [410]. Additinally, a recent pilt study bserved lwer breast density with a greater intake f dietary lignans* [415]. Dense breasts are a risk factr fr breast cancer. Flax has been shwn in vitr and in human trials t decrease tumr prliferatin f breast cancer cells [410, 416]. An animal study reprted that flaxseed inhibited established human breast cancer grwth and reduced incidence f metastasis by 45% [409]. Tumr grwth was reduced by 26% and 38%, respectively, when mice cnsumed a 5% flaxseed diet and 10% flaxseed diet cmpared with thse wh ate n flaxseed [411]. This effect may be partially due t its dwnregulatin f IGF-I [409, 411, 417], decreased cell prliferatin [409, 416, 418], and increased apptsis* [409, 416, 418]. Cnsumptin f flaxseed r flax bread, at least weekly, was assciated with ~20% reductin in the risk f breast cancer [419]. Flaxseed il enhanced the effectiveness f Herceptin in mice [420]. Flaxseed il with lw dse Herceptin was as effective as high dse Herceptin. GREEN TEA Tea cntains phytnutrients* knwn as plyphenls* (flavnids) that prvide antixidant* and anticancer prperties [421]. May blck the frmatin f cancer-causing nitrsamines* [422]. Prevents DNA damage [423]. May inhibit tumr grwth and induce apptsis* [ ]. Increase immune respnse [425]. Epigallcatechin gallate (EGCG) alters gene expressin t lwer the risk f breast cancer [427]. There is a significant amunt f in vitr and in viv evidence suggesting tea plyphenls* have chempreventive actins against varius cancers [424, ]. Mre human data is needed. Green tea and its catechin* cmpnents inhibit breast cancer grwth and angigenesis* in bth cell and animal studies. Studies suggest green tea extract has been successful inhibiting cell prliferatin and breast cancer [421]. Many studies indicate a lwer risk f breast cancer with green tea cnsumptin, but mre research is needed fr cnclusive evidence [ ]. EGCG has been shwn in human studies t inhibit human breast cancer cell prliferatin, reduce tumr invasin and metastasis and prevent recurrence f breast cancer in early stage cases (stage I & II) [ ]. 34

35 A meta-analysis* reprted that drinking green tea decreased the risk f breast cancer by 22% when cmparing wmen with the highest vs lwest intake [430]. A case-cntrl study* fund that green tea cnsumptin was assciated with a significant reductin in risk f breast cancer [433]. Risk by 13% fr wmen cnsuming g f dried green tea leaves annually. Risk by 32% fr wmen cnsuming g f dried green tea leaves annually. Risk by 41% fr wmen cnsuming g f dried green tea leaves annually. Risk by 39% fr wmen cnsuming 750 g f dried green tea leaves annually. Mrever, prtectin was greater with a lnger duratin f drinking green tea, a greater number f cups cnsumed and the mre new batches prepared daily. Hwever, cmbined studies f 35,000 Japanese wmen fund that green tea did nt affect risk f breast cancer [438]. Research suggests that while green tea did significantly decrease tumr mass, when green tea was cmbined with sy phytnutrients*, the tumr mass decreased even further [439]. Further evidence indicates a pssible synergistic relatinship between sy and green tea cnsumptin [432]. Similarly, a synergistic effect f green tea and Ganderma lucidum mushrm extracts n the suppressin f grwth and invasiveness f metastatic breast cancers was bserved [440]. Additinally, green tea increased the inhibitry effect f tamxifen n the prliferatin f ER + breast cancer cells [ ]. Furthermre, sme evidence suggests that the assciatin f tea catechins* and breast cancer may depend n specific gentypes [432]. SOY Assciated with reduced rates f heart disease [ ], prtectin against steprsis [ ], and certain types f cancer, including breast cancer [ ]. While there has been cntentin regarding sy and breast cancer, research findings are predminantly neutral [ ], if nt prtective [8, 450, ]. The majrity f shrt-term sy interventin studies cnducted in premenpausal wmen shw a reductin in endgenus* estrgen levels in assciatin with sy intake, and thus, pssibly prtecting frm breast cancer. The cnflicting data n the effects f sy isflavnes and breast tumr grwth are based n cell studies. Recent human research has been mre prmising. A study f 3,088 breast cancer survivrs ver 7.3 years shwed that wmen with the highest isflavne intake f >16.3 mg/day had a 54% reductin in risk f death [452]. Similarly, a prspective study cncluded that the highest sy isflavne intake was assciated with decreased breast cancer mrtality in the Chinese ppulatin [457]. 35

36 A case-cntrl* study in China shwed that the highest relative sy isflavne intake was assciated with a 58% decrease risk f breast cancer, and the highest intake f sy prtein decreased breast cancer risk by 54% [450]. Interestingly, these results were strngest in pstmenpausal wmen and ER+/PR+ wmen. A statistically significant inverse assciatin between plasma genistein and breast cancer was reprted amng Japanese wmen [454]. A recent meta-analysis f well-cntrlled studies that included high-sy-cnsuming Asians reprted a significant trend f decreasing risk with increasing sy fd intake. Risk was lwest amng thse wh cnsumed 20 mg isflavnes daily [455]. High sybean intake in Krean wmen resulted in a significantly lwer risk f breast cancer in pstmenpausal wmen [8]. Pstdiagnsis sy cnsumptin f greater than 10 mg sy isflavnes daily significantly reduced the risk f recurrence amng bth US and Chinese wmen [459]. Additinally, breast cancer mrtality and verall mrtality were nnsignificantly reduced. In a large ppulatin based chrt study f ver 5000 breast cancer survivrs in China, sy fd intake was inversely assciated with mrtality and recurrence [460]. This assciatin was evident amng wmen with either ER+ r ER- breast cancer and was present in bth users and nnusers f tamxifen. It s becming mre apparent that the timing f sy expsure is critical. Cnsumptin f sy fds r an expsure t a sy isflavne genistein during childhd and adlescence in wmen, and befre puberty nset in animals, appears t reduce the risk f breast cancer later in life [462]. The type f sy cnsumed may prvide sme insight t the incnsistent findings. It has been demnstrated that sy prcessing increases tumr grwth in mice fr pstmenpausal ER+ breast cancer [463]. The difference in tumr grwth bserved may be related t isflavne metablism and biavailability, but mre research is needed [464]. Nnetheless, these studies suggest that WHOLE SOY FOODS appear t nt have a negative effect n pstmenpausal ER+ breast cancer. A recent chrt* study f breast cancer patients fund that sy fds had n negative impact n breast cancer survival [ ]. An Asian-American study n sy fund that wmen, pre- and pstmenpausal, wh cnsumed tfu, had a 15% reduced risk f breast cancer with each additinal serving per week [448]. Mrever, a recent trial reprted that wmen in the highest tertile intake f tfu had a 51% decrease risk f premenpausal breast cancer when cmpared with wmen in the lwest tertile [449]. N statistical significant assciatin was bserved between sy intake and breast cancer risk amng pstmenpausal wmen. A prspective trial reprted breast cancer mrtality reduced 36-38% with an average intake f sy isflavne abve 17.3 mg/day [467]. Furthermre, prgnsis was better fr wmen with ER+ tumrs with a high intake f sy isflavnes. A meta-analysis* f 35 studies analyzing the assciatin between sy intake and breast cancer risk discvered that sy isflavne intake lwered the risk f breast cancer fr bth pre- and pstmenpausal wmen in Asian cuntries, but the evidence was nnsignificant fr wmen in Western cuntries [453]. Thus, regin culd als be significantly influencing results. 36

37 Sy cnsumptin has been suggested t exert ptential cancer-preventive effects in premenpausal wmen, such as increased menstrual cycle length and SHBG* levels and reduced estrgen levels. 40 mg/day sy isflavnes increased menstrual cycle length in Western wmen [468]. Research als suggests that sy isflavnes may significantly imprve the 2-hydrxyestrne:16- a-hydrxyestrne rati [469]. Additinally, sy intake increases time spent in the fllicular cycles, when prliferatin is at its lwest [468]. Furthermre, vegan prtein surces, such as sy, appear t decrease circulating IGF-I activity, which may impede cancer inductin [444, ]. Recent literature assessing the effects f sy and tamxifen have yielded neutral [472] r beneficial findings [473]. In a study f Asian American breast cancer survivrs n tamxifen, sy intake had n effect n levels f tamxifen r its metablites [472]. The cmbinatin f tamxifen and genistein inhibited the grwth f ER+/HER2- human breast cancer cells in a synergistic manner in vitr [473]. In a randmized placeb-cntrlled study, it was fund that gene expressin assciated with sy prtein intake and high plasma genistein is due t an verexpressin f FGFR2 and cell cycle prliferatin genes, leading t the cnclusin that sy can adversely affect wmen with this type f gene expressin [474]. Surce Amunt f Sy Prtein (gm) Mis (1 tbsp) * Sybeans, edamame (1/2 cup) 11 35* Sy milk (8 fl z) 10 23* Sy nuts (1/4 cup) * Tempeh (1/2 cup) * Tfu (4 z) 13 39* * Isflavne cntent varies by brand Amunt f Sy Isflavnes (mg) Vitamin D Epidemilgical studies suggest an inverse relatinship between sun expsure, serum levels f 25(OH)-vitamin D, and vitamin D intake and the risk f develping and/r surviving cancer [ ]. Pssible mechanisms t explain the prtective effects f vitamin D may be its rle as a nuclear transcriptin factr that regulates cell grwth, differentiatin, apptsis and a wide range f cellular mechanisms central t the develpment f cancer. Furthermre, breast density, a factr that may increase the risk f breast cancer, was inversely assciated with vitamin D intake [477]. 37

38 The wmen in the Nurses Health Study bserved a 30% reductin in risk f breast cancer cmparing the highest with lwest quintiles f 25(OH)-vitamin D levels [478]. Pst-menpausal breast cancer risk was significantly inversely assciated with serum 25(OH)- vitamin D levels [479]. Risk decreased as wmen s levels increased frm 30 nm (12 ng/ml) t 75 nm (30 ng/ml). A meta-analysis* f prspective studies reprted that with a 5 ng/ml increase in 25(OH)-vitamin D levels, vitamin D was assciated with a 12% lwer risk f breast cancer, with suggestive flattening at higher dses (>35 ng/ml) [480]. A case-cntrl* study in China fund that wmen with the highest quartile 25(OH)D level shwed a significant decreased breast cancer risk and every 1 ng/ml increment f plasma 25(OH)D level led t a 16% lwer dds f breast cancer [481]. In a ppulatin-based case-cntrl* study, dietary vitamin D intake was psitively assciated with breast cancer, whereas vitamin D supplement use was inversely assciated with breast cancer [482]. These assciatins were bserved fr ER+/PR+ and ER-/PR- breast cancers, but nt fr ER+/ PR- disease. Larger tumr size at diagnsis significantly crrelated with lwer 25(OH)-vitamin D serum levels [483]. Additinally, pstmenpausal wmen with higher 25(OH)-vitamin D levels had an imprved breast cancer-specific utcme. Three meta-analyses* shwed that high bld 25(OH)-vitamin D levels in breast cancer patients were significantly assciated with lwer breast cancer mrtality [ ]. 25(OH)-vitamin D levels >30 ng/ml in breast cancer patients were assciated with significantly lwer mrtality [487]. It is nw believed that the recmmended vitamin D dse shuld be between 1,000 and 5,000 IU per day, and in sme cases, even higher. Research indicates that vitamin D3 (chlecaciferl) is better absrbed than vitamin D2 (ergcalciferl) [488]. Due t the likelihd f a bichemical deficiency withut clinical symptms r signs, a serum 25(OH)-vitamin D level is recmmended. Optimal serum 25-hydrxy vitamin D levels have nt been established thugh research suggests that restring levels t ng/ml may be ideal [485]. Earlier research had suggested ng/ml [489]. While supplementatin may be recmmended, mre apprpriate dsing f vitamin D supplementatin can be made nce a serum 25(OH)-vitamin D level has been established. 38

39 Fd r Beverage Summary Recmmendatin Flaxseed Gd surce f mega-3 fatty acids and fiber, cntains prtein, calcium, ptassium, B vitamins, irn, and brn. 2 Tbsp grund flaxseed daily Green tea Opt fr grund flax seeds rather than whle flax seeds, flax seed il, flax supplements t increase biavailability. Flax seeds may be grund in a cffee grinder, blender, r fd prcessr. Green tea cntains des cntain caffeine thugh much less than cffee r black tea. Flax can have a laxative- like effect, thus, it is wise t gradually increase cnsumptin. Sprinkle int varius fds and beverages, including ht cereals, tmat sauces, fruit smthies, brwn rice r ther grains. Stre flax in the refrigeratr r freezer. 1-4 cups daily Sy Vitamin D If pting fr decaffeinated green tea, pt fr thse naturally decaffeinated with water as typical caffeine extractin results in a significant lss f phytnutrients. Cntains varius nutrients, including prtein, fiber, calcium, and B vitamins. Rich in antixidants*, knwn as isflavnes, namely genistein and daidzein. Amng thers, dietary surces include sybeans, edamame, tfu, symilk, tempeh, mis, and sy nuts. A fat-sluble vitamin that we generate thrugh skin synthesis f sunlight (ultravilet rays). Dietary surces include cld-water fish, eggs, and frtified prducts, such as milk, sy milk, and cereals. Unless sy has been a part f yur diet fr years, pstmenpausal individuals with ER+ breast cancer may be advised t limit sy cnsumptin t 1-3 daily servings. Sy supplements r isflavne extracts are nt recmmended. 1,000-4,000 IU daily Maintain serum 25 (OH)-vitamin D >40 ng/ml. MELATONIN Melatnin is a hrmne prduced by the pineal gland. Its primary functin invlves the regulatin f the bdy s circadian rhythm, endcrine secretins, and sleep patterns. Sme research indicates that individuals with lw levels f melatnin are at greater risk fr breast cancer. The risk f breast cancer was reduced by 33% in pstmenpausal wmen wh slept 9+ hurs cmpared t thse wh slept 6 hurs daily [500]. 39

40 Melatnin levels were 42% higher in thse wh slept 9+ hurs vs 6 hurs daily. Previus studies have reprted an increased risk f breast cancer in night-shift wrkers wh are expsed t light at night [ ]. It may be that the length f time wrking night shifts makes a difference as evidenced by this study where wmen wh reprted mre than 20 years f rtating night shift wrk faced an increased risk f breast cancer cmpared with wmen wh did nt reprt any rtating night shift wrk [502]. In vitr and animal research has supprted the prtective effect f melatnin against breast cancer [ ]. A recent study fund that wmen with higher urinary melatnin levels had a 30-41% reduced risk f breast cancer [506]. Melatnin may act by: Inhibiting cell prliferatin [505, ]. Inducing apptsis* [509]. Inhibiting angigenesis* [505]. Enhancing the immune system [507, ]. May imprve survival in cancer patients by prtecting the immune system frm damage caused by chemtherapy [509]. Reducing IGF-I [ ]. Decreasing the number and activity f estrgen receptrs, thus reducing ways that the cancer cell cnnects t estrgen [ ]. Specifically, recent studies shw that melatnin suppresses estrgen prductin in breast adipse fibrblasts, and lwer levels f melatnin in aging wmen may increase ER+ breast cancer [516]. Varius studies indicate that melatnin may inhibit breast cancer by interfering with estrgen pathways, thus acting in an anti-estrgenic manner [508, 510, ]. Melatnin decreases the frmatin f estrgen frm andrgens by inhibiting armatase activity [508]. Furthermre, the cmbinatin f melatnin and retinids* [519], the cmbinatin f all-trans retinic acid, smatstatin, and melatnin [520], and the cmbinatin f melatnin and vitamin D3 [521] appear t wrk synergistically t inhibit the grwth f breast cancer cells. Melatnin des have bld thinning prperties, thus it is recmmended t nt use supplemental melatnin 7-10 days prir t surgery. FOOD SAFETY Especially imprtant fr thse with weakened r impaired immune systems and while n chemtherapy. The fllwing recmmendatins have been adapted frm guidelines prvided by the American Cancer Sciety. Wash fds thrughly befre eating. 40

41 Keep all aspects f fd preparatin meticulusly clean. Use special care in handling raw meats, pultry, and eggs. Thrughly clean all utensils, cuntertps, cutting bards, and spnges that cntacted raw meat. Thaw meats and fish in the refrigeratr. Transfer large vlumes f leftvers, such as sup, rice, r casserles, t shallw cntainers and place in refrigeratr. This prcess ensures prper cling. D nt eat perishable fds that have been left ut f the refrigeratr fr mre than tw hurs. Stre fds at lw temperatures (less than 40 F) t minimize bacterial grwth. When eating in restaurants, avid fds that may have bacterial cntaminatin, including sushi, salad bars, buffets, unpasteurized beverages r fd prducts, and raw r undercked meat, pultry, fish, and eggs. BONE HEALTH Pre- and pstmenpausal survivrs f breast cancer are at great risk fr develpment f steprsis. Thus, screening and preventive strategies fr steprsis are imperative. Even small amunts f increased bne mass prvide great risk reductin fr fractures. Generally, humans reach peak bne mass arund 30 years. After the age f 30, the gal is t maintain r prevent lss f bne mass. On average, humans lse % bne mass yearly after 30 years. First signs f steprsis are seen in spine, hip, and wrist. Symptms include back pain r tenderness, lss f height, and slight curving f upper back. Risks fr steprsis include: female, Asian r white ethnicity, age, menpause, amenrrhea, lw teststerne levels in men, sedentary lifestyle, family histry, diet lw in calcium, diet lw in vitamin D, excessive alchl and tbacc use, excessive caffeine use, diet high in sdium, diet excessive in prtein r very lw in prtein, certain medicatins (diuretics, sterids, thyrid meds), celiac disease Many nutrients have bne-building effects, including calcium, vitamin D, phsphrus, magnesium, vitamin K, ptassium, and brn (see table belw). Exercise increases bne mass befre menpause and slws bne lss after menpause. Include weight-bearing exercise, such as walking, jgging, skiing, stair climbing, aerbics, and thers. Resistance training exercises are useful t strengthen muscles and bnes. Recent research indicates diets high in fruits and vegetables have a psitive effect n bne health. Gd surce f minerals (ptassium, magnesium) that may have direct effects n bne cells. Cunteract acid envirnment. Lwer urinary calcium lss. 41

42 Enhanced calcium biavailability f mst vegetables. Sy prtein and/r sy isflavnes have been prpsed t delay bne lss. May help t prevent urinary calcium lss. Sy cntains phytsterls that mimic the actins f estrgen. May help t prevent rapid bne lss f menpause years. Studies reprt that sy may increase BMD. Calcium supplements Take 500 mg r less per meal t maximize absrptin. Calcium citrate, lactate, r glucnate are recmmended if yu have irn deficiency. These d nt decrease irn absrptin like calcium carbnate. Calcium carbnate is least expensive, but may increase gas and blating in sme individuals. What abut antacids with calcium? Trace minerals like zinc r irn may be less well-disslved and absrbed with a lwer stmach acidity. If yu re nly taking enugh antacid fr the purpse f calcium needs, shuld nt present a majr prblem, but nt ideal. May interact with thyrid medicatin. DEXA (dual-energy X-ray absrptimetry) instruments allw rapid, painless, nninvasive, and highly reprducible measurements f bne density t be made [522]. These measurements are used t diagnse steprsis, lw bne density, and risk f fracture and t determine rates f bne lss r the effectiveness f treatment ver time [ ]. Bne Health Bttm Line Balanced diet high in fruits and vegetables Calcium Aim fr 3 rich surces daily. Include a supplement if necessary. Vitamin D Meet needs frm sun, multivitamin, r ther supplement. Cnsider serum vitamin D test. Exercise Weight-bearing exercise fr at least 30 minutes n mst days. Gd psture Request t have a full bdy DEXA scan. 42

43 Bne Building Nutrients Nutrient* Dietary Surces Functin Recmmendatin Calcium Dairy prducts, canned fish with sft bnes, beans, leafy greens (especially cllard calcium absrptin and biavailability frm fds, especially plant surces mg daily greens, bk chy, and Vitamin D is essential kale), tfu, almnds, fr calcium absrptin. frtified prducts, such as sy milk, cereal, and range juice Vitamin K Dark leafy greens, liver, tmates, sybeans, and garbanz beans Assciated with bne turnver and urinary calcium excretin. 90 mcg daily Als prduced by intestinal bacteria Phsphrus Meat, pultry, fish, eggs, milk, prducts, legumes, and nuts Cmbines with calcium t strengthen bnes. 700 mg daily Magnesium Whle grains, nuts, seeds, spinach, and mst fruits and vegetables Imprtant in calcium and ptassium uptake. 320 mg daily Ptassium Bananas, strawberries, tmates, prunes, ptates, spinach, and beans Assciated with urinary calcium and phsphrus excretin mg daily Brn Apples, avcads, beans, milk, peanuts, peanut butter, pecans, raisins, prunes, and ptates Imprves calcium absrptin. effects f vitamin D and magnesium deficiency. 2 mg daily Zinc Seafd, meats, tfu, whle grains, blackeyed peas, wheat bran and germ Imprtant in calcium uptake and immune functin mg daily * Vitamin D is listed in the previus table 43

44 Ht Flashes Ht flashes are a majr cause f mrbidity amng pstmenpausal wmen, including many survivrs f breast cancer. Apprximately 75% f pstmenpausal wmen wh had breast cancer reprt experiencing ht flashes [525]. Mre than 90% f yung survivrs als experience ht flashes, which can be mre severe and lng lasting, with iatrgenic varian ablatin r antiestrgen therapy. A crss-sectinal study f 300 breast cancer survivrs shwed that wmen wh gained at least 10 lbs since breast cancer diagnsis were twice as likely t have ht flashes than thse wh maintained r lst weight [526]. Varius nn-hrmnal therapies have been studied fr imprving ht flashes, including sy, black chsh, red clver, and vitamin E the clinical value has been limited. Supplemental vitamin E at 400 IU/day [527] and 800 IU/day [528] has shwn sme limited efficacy in imprving ht flashes. Systematic reviews f randmized cntrlled trials have bserved cntradictry results, and meta-analyses* demnstrate n statistically significant reductin f vasmtr symptms fr phytestrgens [529]. Individual trials reprt significant reductins in vasmtr symptms fr red clver and sy phytestrgens. The placeb effect in many f these studies was quite strng [530]. Studies assessing black chsh and red clver have had incnsistent results, with sme trials shwing benefit and sme n difference cmpared with placeb [531]. In ne study, wmen receiving black chsh reprted a mean decrease in ht flash scre f 20% cmpared with a 27% decrease fr patients n placeb [532]. Mean ht flash frequency was reduced 17% n black chsh and 26% n placeb. A previus study reprted reduced ht flashes with sy isflavnes by 9 t 40% in sme trials, but mst trials bserved n effect when cmpared with placeb [531]. Black chsh extract had n effect n serum estrgenic markers [533]. The use f black chsh appears t be safe in breast cancer patients [534]. Psycheducatinal interventins, including relaxatin, seem t alleviate ht flashes in menpausal wmen and breast cancer survivrs; hwever, the methdlgical quality f published research has been cnsidered t be fair r pr [535]. A summarizatin f six prspective studies shwed a 43.2% reductin f ht flashes frm baseline t the end f acupuncture treatment; effects cntinued n fr at least 3 mnths after the end f acupuncture treatment [536]. A preliminary study f 25 breast cancer patients reprted that 400 mg-800 mg magnesium xide fr 4 weeks resulted in a ht flash scre reductin f 50.4% and frequency reductin by 41.4% [537]. Nte that magnesium glycinate wuld be the preferred magnesium surce given its increased biavailability. 44

45 WORDS OF WISDOM Let fd be yur medicine and medicine be yur fd. - Hippcrates Fr additinal infrmatin r resurces, please visit the Ida and Jseph Friend Cancer Resurce Center at 1600 Divisader St. n the first flr, r call at (415) The infrmatin in this publicatin is designed fr educatinal purpses nly and is nt intended t replace the advice f yur physician r health care prvider, as each patient s circumstances are individual. We encurage yu t discuss with yur physician any questins and cncerns that yu may have. Three Day Menu Plan: 3 Meals + Snack This menu is based n 1600 calries, calries can be adjusted by altering prtin sizes. The menu has been designed t merely serve as a guide in making healthy fd chices. Experiment with substitutins as desired. Day 1 Day 2 Day 3 Oatmeal, cked (1cup) Nn-dairy milk (1 cup) Flaxseed, grund (1 tbsp) Chia seeds (1 tbsp) Blueberries (1/2 cup) Egg, hard biled (1 lg) Green tea (2 cups) Salad Spinach (3 cups) Brccli (1/2 cup) Carrts (1/2 cup) Tmat (1/2 cup) Chicken breast (4 z) Barley, cked (1/2 cup) Avcad (4 slices) Olive il (1/2 tbsp) Vinegar, balsamic (1 1/2 tbsp) Green Smthie Greens (3 cups) Berries, frzen (1/2 cup) Prtein pwder (1 svg) Grund flax (1-2 tbsp) Chia seed (1 tbsp) Almnd milk, unsweetened (3/4 cup) Vegetable Bean Sup (2 cups) Crn trtilla (1 med) Green salad (2 cups) Oil/vinegar dressing (1 tbsp) Egg scramble Eggs (2 lg) Onins (1/4 cup) Spinach (1 cup) Mushrms (1/2 cup) Apple (1 med) Almnd butter (1 tbsp) Green tea (2 cups) Black bean crn salad (2 cups) ver steamed kale (1 cup) Orange (1 med) Vegetable juice (12 z) Ppcrn, air-ppped (2 cups) Tempeh fajitas (4 z) Onins & peppers (1.5 cups) Salsa (1/4 cup) Avcad (1/4 ea) Crn trtillas (2 each) Fruit salad (1 cup) Almnds (1/4 cup) Chicken & vegetable stir-fry Chicken breast (4 z) Mixed vegetables (2 cups) Walnuts (2 tbsp) OR Olive il (1/2 tbsp) Brwn rice, cked (1 cup) 45 Fruit smthie Banana (1/2 med) Berries (1/2 cup) Flaxseed, grund (2 tbsp) Chia seeds (1 tbsp) Ygurt, Greek plain (1/2 cup) Nn-dairy milk (1 cup) Salmn (4 z) Quina, cked (1 cup) Asparagus (2 cups)

46 Recipes Green Smthie Ingredients: 3-5 cups greens (spinach, kale, cllards, r ther) 1 tbsp chia seeds 1-2 tbsp grund flax seeds 3/4 cup unsweetened almnd milk 1/2 cup frzen blueberries (r ther fruit) 1 serving unsweetened prtein pwder Place liquid in blender fllwed by the remaining ingredients. Blend and enjy! Makes 16 unces. Nutritin Infrmatin (per 16 z): Calries: 363 Dietary fiber: 15gm Prtein: 30 gm Sdium: 300 mg Fat: 14.6 gm Calcium: 633 mg Saturated fat: 1.6 gm Irn: 5 mg Carbhydrates: 34 gm Recipe develped by Natalie Ledesma, MS, RD, CSO Baked Tfu Ingredients: 1pund tfu,firm, drained 3 tablespns lw sdium tamari r ther sy sauce 1 teaspn tasted sesame il 2 clves garlic, minced 1 teaspn finely minced gingerrt 1/2 teaspn red pepper flakes 1 teaspn brwn rice syrup r dark brwn sugar Chp drained firm tfu int 1 cubes. Place tfu cubes in glass dish fr baking. Pur marinade r sauce ver tfu, stir well. Place tfu in ven at 350 F fr 1 hur. Stir every minutes. Makes fur 4-unce servings. Nutritin Infrmatin (per 4 z serving): Calries:120 Dietaryfiber: <1gm Prtein:8 gm Sdium:575 mg Fat:5 gm Calcium: 155mg Saturated fat:<1 gm Irn:1.4 mg Recipe frm the Hippy Gurmet s Quick and Simple Ckbk fr Healthy Eating 46

47 Washingtn Insider Salad Ingredients: 1 can (15 z) kidney beans, drained 1 can (15 z) black eyed peas, drained 1 1/2 cups cked barley (substitute quina, wild rice, r brwn rice t make gluten free) 6 tbsp cilantr, chpped finely 1 can (11 z) crn 1 1/2 cups tmates, diced 3 tbsp balsamic vinegar 2 tbsp live il Prepare vegetables. Mix all ingredients tgether, and serve n a bed f dark green leafy lettuce. Add salt and pepper t taste. Makes 8 servings (1 cup each). Nutritin Infrmatin (per serving): Calries: 215 Prtein: 10 gm Fat: 4 gm Dietary fiber: 9 gm Recipe develped by Sus Chef Chris at the Occidental Grill, Washingtn D.C. Spinach Spread Ingredients: 1 package (10.5 unces) silken tfu 1 tbsp lemn juice 1/4 tsp garlic pwder 3/4 tsp nin pwder 1/2 tsp dried tarragn 1/4 tsp salt 1 bx (10 unce) frzen chpped spinach, thawed 1 cup carsely shredded carrts 1/4 cup chpped green nin Puree the tfu and lemn juice in blender until smth. Whirl in the garlic and nin pwders, tarragn, and salt just t blend. Scrape int a mixing bwl. Squeeze the spinach as dry as pssible. Stir it int the tfu, alng with the carrts and green nin. Mix well. Serve with crackers, pita triangles, r vegetables. Makes 8 servings (1/4 cup each). Nutritin infrmatin (per serving): Calries: 39 Sdium: 82 mg Fat: 1 gm Calcium: 51 mg Saturated fat: 0 gm Carbhydrate: 5 gm Prtein: 4 gm Dietary Fiber: 2 gm Recipe frm the U.S. Syfds Directry. 47

48 Curried Hummus Ingredients: 1/4 cup currants 2 cups cked chickpeas, r 1 15-unce can, drained and rinsed 2 tbsp water 2 tbsp freshly squeezed lemn juice 1 tbsp tahini 1 tbsp extra-virgin live il 1 tsp curry pwder 1 tsp grund ginger ½ tsp sea salt Place the currants in a small bwl f ht water t sak and plump up. Cmbine the chickpeas, water, lemn juice, tahini, live il, curry pwder, ginger, and salt in a fd prcessr and prcess until smth. Transfer t a mixing bwl and adjust the seasning t taste. Add a spritz f lemn if it needs a little extra zing. Befre serving drain the currants thrughly and stir them int the hummus. Serve with chpped, raw vegetables r whle grain crackers. Makes 6 servings. Nutritin Infrmatin (per serving): Calries: 180 Carbhydrate: 27 gm Prtein: 7 gm Dietary fiber: 7 gm Fat: 5.7 gm Sdium: 630 mg Recipe frm The Cancer-Fighting Kitchen by Rebecca Katz. Alaska Salmn Bake with Walnut Crunch Cating Ingredients: 1 pund salmn fillets, thawed if necessary 2 tbsp Dijn-style mustard 1-2 tbsp live il 4 tsp hney 1/4 cup bread crumbs 1/4 cup walnuts, finely chpped 2 tsp parsley, chpped Salt and pepper t taste Lemn wedges Mix tgether mustard, live il, and hney in a small bwl; set aside. Mix tgether bread crumbs, walnuts, and parsley in a small bwl; set aside. Seasn each salmn fillet with salt and pepper. Place n a lightly greased baking sheet r briling pan. Brush each fillet with mustard-hney mixture. Pat tp f each fillet with bread crumb mixture. Bake at 450 F fr 10 minutes per inch f thickness r until salmn just flakes when tested with a frk. Serve with lemn wedges. Makes 4 servings (4 z each). 48

49 Nutritin Infrmatin (per serving) Calries: 228 Prtein: 20 gm Fat: 12 gm Omega-3 fatty acids: 1.7 gm Adapted frm Alaska Seafd Marketing Institute. Pumpkin Oat Bars Ingredients: 3 cups gluten free r regular ld fashined ats 2 tsp baking pwder 1/2 tsp baking sda 1/4 tsp salt 1 1/4 tsp cinnamn 1/8 tsp nutmeg pinch f grund clves 1 cup canned pumpkin 2 tsp pure vanilla extract 1/2 cup unsweetened applesauce 1/2 cup dark brwn sugar 1 tbsp melted ccnut il ptinal: 1/3 cup regular chclate chips, dried cranberries, raisins, walnuts Preheat ven t 350 degrees F. Spray 8 11 r 9 inch baking pan with nnstick cking spray. Make at flur: Place atmeal int blender r fd prcessr and blend fr 1-2 minutes until atmeal resembles flur. Yu may need t stp blender and stir ats a cuple f times t ensure that all ats have been blended. Place at flur in a medium bwl. Whisk in baking pwder, baking sda, salt and spices; set aside. In a separate large bwl, whisk tgether pumpkin, brwn sugar, vanilla extract, il, and applesauce fr 1-2 minutes until the cnsistency is smth and creamy. Slwly add in at flur mixture and mix until just cmbined. If using, gently fld in 1/3 cup f chclate chips, dried fruit, and/r nuts. Pur batter int prepared pan. Bake fr minutes r until knife inserted int center cmes ut clean r with just a few crumbs attached. Timing will depend n what size pan yu use, but definitely check arund 15 minutes. Once finished baking, cl 10 minutes n wire rack. Cut int 16 slices. Nte: Bars can be frzen. Makes 16 servings. Nutritin Infrmatin (per serving): Calries: 107 Carbhydrate: 20 gm Prtein: 3 gm Dietary fiber: 2.6 gm Fat: 2 gm Sdium: 146 mg Adapted frm the Ambitius Kitchen Blg. 49

50 Dilled Salmn Salad with Peas Ingredients: 1 can (15 z) salmn, drained 1 package (16 z) frzen peas, thawed 1/4 cup lemn juice 1/4 cup fresh dill (r 1-2 tbsp dried dill) 2 tbsp Dijn-style mustard 2 shallts, sliced thinly (abut 1/2 cup) 1 bunch radishes (abut 11 medium), thinly sliced 6 cups red leaf lettuce Salt and pepper t taste Drain salmn, place in a mixing bwl, and break int pieces. Prepare the lemn juice, shallts, radishes, and lettuce. Add t the salmn the peas, lemn juice, dill, mustard, shallts, and radishes. Mix tgether gently. Add salt and pepper t taste. Serve salmn mixture ver lettuce. Makes 6 servings (2 cups each). Nutritin Infrmatin (per serving): Calries: 160 Prtein: 17 gm Fat: 4 gm Dietary fiber: 5 gm Adapted frm the Wmen s Healthy Eating & Living Study (WHEL) at the University f Califrnia, San Dieg. Develped by Vicky Newman, MS, RD, WHEL nutritin crdinatr. Neat Laf Ingredients: 2 cups cked brwn rice 1 cup walnuts, finely chpped 1 nin, finely chpped 1/2 medium bell pepper, finely chpped 2 medium carrts, shredded r finely chpped 1 cup wheat germ (culd substitute flax seed r almnd meal t be gluten-free) 1 cup quick-cking rlled ats 1/2 tsp each: thyme, marjram, sage 2 tbsp sy sauce (r gluten-free tamari) 2 tbsp stne grund r Dijn mustard Barbecue sauce r ketchup Preheat the ven t 350 F. Cmbine all the ingredients except the barbecue sauce r ketchup. Mix fr 2 minutes with a large spn. This will help bind it tgether. Pat int an il-sprayed 5x9 lad pan and tp with barbecue sauce r ketchup. Bake fr 60 minutes. Let stand 10 minutes befre serving. Makes 8-10 servings. 50

51 Nutritin Infrmatin (per serving): Calries: 204 Sdium: 248 mg Prtein: 9 gm Chlesterl: 0 mg Fat: 9 gm Carbhydrates: 19 mg Recipe frm The Peaceful Palate written by Jennifer Raymnd. Raw Kale Salad with Aged Balsamic Vinaigrette Ingredients: 1 large bunch (abut 1 pund) lacinat kale (als called dinsaur r Tuscan kale) Ksher salt and freshly grund pepper 2 tsp Dijn mustard (ptinal) 2 tbsp gd quality balsamic vinegar 1/4 cup extra-virgin live il Juice f 1/2 lemn (ptinal) 1 medium shallt, finely chpped (ptinal) A handful tasted nuts such as almnds r walnuts (abut 1 unce r 1/4 cup) 1 apple, chpped r a handful dried fruit such as currants, cranberries, raisins, dried cherries, etc (abut 1 unce r 1/4 cup) Strip the leaves ff the stems. (Save the stems fr anther use such as green smthies.) Wash and pat dry the leaves. Stack the leaves and cut them crsswise int strips abut 1/4 inch wide. Pile the kale in a salad bwl and sprinkle with 1/4 teaspn salt. With clean hands, massage the salt int the leaves until the kale begins t feel mist and darken a bit, abut 2 r 3 minutes. Yu can d this well ahead f time, cver the salad with plastic wrap, and leave at rm temperature r refrigerate fr several hurs. In a small bwl, whisk tgether the mustard and vinegar. Grind in sme pepper and then whisk in the il. Taste fr balance and add as much lemn juice, salt, and pepper as needed t create a vibrant, fresh, sweet/tart balance. G easy n the salt t accunt fr the salt already n the kale. When ready t serve, tss the greens with the dressing, shallts, apple r dried fruit, and nuts. Serve immediately. Serves 6 t 8 Nutritin Infrmatin (per serving - 1/6 recipe): Calries: 180 Sdium: 382 mg Prtein: 4 gm Chlesterl: 0 mg Fat: 13 gm Dietary fiber: 2 gm Carbhydrate: 15 gm Recipe adapted frm Living On, Living Well, UCSF Survivrship Retreat by Penni Wisner, The Kitchen Cach. 51

52 Quina/ Sweet Ptat Patties Ingredients: 1 1/2 cups sweet ptat, peeled and chpped 1 cup quina 2 tbsp parsley, fresh 1/2 tsp sea salt 2 tsp extra-virgin live il Steam r bake sweet ptates until dne. Drain and mash ptates. Wash the quina well and drain. Dry tast the quina in a skillet until slightly brwned. Meanwhile, bring a pt f water t a bil. Add the tasted quina t the biling water and ck, with lid ff, fr ~15 minutes. Drain well. Mix the mashed ptates and quina. Add the parsley and salt. Frm 8 patties and place in a lightly iled pan ver medium-high heat. Ck fr abut 5 minutes n each side and serve warm. Makes 8 servings. Nutritin Infrmatin (per serving): Calries: 125 Sdium: 165 mg Prtein: 4 gm Chlesterl: 0 mg Fat: 2 gm Carbhydrate: 22 gm Recipe adapted frm the Vegetarian Resurce Grup. Ccnut Quina Chia Granla Ingredients: 1 cup rlled ats (r steel cut ats) 1/2 cup quina, uncked 1/2 cup almnds, carsely chpped/slivered/sliced 1/4 cup chia seeds 1/8 tsp sea salt 3 tbsp ccnut il 3 tbsp maple syrup 1 tsp vanilla extract 1/4 cup ccnut flakes, unsweetened Preheat ven t 325 degrees F and line baking sheet with parchment paper. In a medium mixing bwl, add ats, quina, almnds, chia seeds, salt and mix. In a small bwl, melt ccnut il in a micrwave and add maple syrup and vanilla extract. Stir t cmbine and pur int a bwl with dry ingredients. Mix thrughly and spread in an even layer n prepared baking sheet. Bake n a third rack frm the bttm fr 30 minutes. Remve granla frm the ven and sprinkle with ccnut flakes. Let cl cmpletely and d nt tuch. Makes 24 servings. 52

53 Nutritin Infrmatin (per 2 tbsp serving): Calries: 60 Chlesterl: 0 mg Carbhydrate: 7.8 gm Sdium: 15 mg Fat: 2.8 gm Sugars: 1.9 gm Fiber: 1.1 gm Recipe adapted frm the ifdreal.cm. Nutritin Resurces Bks Anticancer: A New Way f Life - written by David Servan-Schreiber (2008) Five t Thrive - written by Lise Alschuler & Karlyn Gazlla (2011) Hw t Prevent & Treat Cancer with Natural Medicine written by Michael Murray (2002) Life Over Cancer - written by Keith Blck (2009) The Clr Cde written by James Jseph, Daniel Nadeau, & Anne Underwd (2002) The UltraMind Slutin - written by Mark Hyman (2009) Ultra Metablism written by Mark Hyman (2006) Ckbks One Bite at a Time written by Rebecca Katz, Marsha Tmassi, & Mat Edelsn (2004) The Cancer-Fighting Kitchen - written by Rebecca Katz with Mat Edelsn (2009) The Cancer Wellness Ckbk - written by Kimberly Mathai (2014) The Healthy Mind Ckbk - written by Rebecca Katz with Mat Edelsn (2015) The UltraMetablism Ckbk - written by Mark Hyman (2007) Newsletters/Magazines Cking Light Fax: (205) Envirnmental Nutritin (800) Nutritin Actin Health Letter Fax: (202)

54 Websites American Cancer Sciety (415) American Institute fr Cancer Research (800) Caring4Cancer - Prvides up-t-date & cmprehensive infrmatin n the cnnectin between nutritin & cancer Cnsumer Lab - Evaluates quality f ver-the-cunter supplements Diana Dyer, MS, RD Breast cancer survivr & dietitian Eating Well - Offers recipes, cking tips, articles regarding health, and mre. cm Harvard Nutritin Surce Ida & Jseph Friend Cancer Resurce Center UCSF Mt.Zin (415) Natinal Cancer Institute (800) 4-CANCER ( ) Onclink Prvides infrmatin regarding clinical trials, newsgrups, psychscial supprt, & mre. Onclgy Nutritin DPG - Prvides articles, recipes, & resurces. San Francisc Vegetarian Sciety Mnthly restaurant utings & pt-luck dinners; call The Vegetarian Resurce Grup - Prvides vegetarian nutritin infrmatin & vegetarian recipes The Wrld s Healthiest Fds - Prvides healthful recipes and basic nutrient infrmatin. WebMD Glssary Angigenesis The frmatin f new bld vessels. Antixidant A substance that inhibits xidatin r inhibits reactins prmted by xygen r perxides. Apptsis Prgrammed cell death. Carcingenesis Beginning f cancer develpment. Case-Cntrl Studies An epidemilgical study in which a grup f, say, cancer patients (cases) is cmpared t a similar but cancer-free ppulatin (cntrls) t help establish whether the past r recent histry f a specific expsure such as smking, alchl cnsumptin and dietary intake, etc. are causally related the risk f disease. Catechin One f the tannic acids; phytnutrient, specifically, ne f the flavnids fund in green tea. Creatine An amin acid that is frmed in the muscle tissue f vertebrates; supplies energy fr muscle cntractin. 54

55 Chrt Studies Fllw-up study f a (usually large) grup f peple, initially disease-free. Differences in disease incidence within the chrt are calculated in relatin t different levels f expsure t specific factrs, such as smking, alchl cnsumptin, diet and exercise, that were measured at the start f the study and, smetimes, at later times during the study. Eicsanids Bilgically active cmpunds that regulate bld pressure, bld cltting, and ther bdy functins. They include prstaglandins, thrmbxanes, and leuktrienes. Endgenus Originating frm within, as within the bdy. Estradil A naturally ccurring pwerful estrgen secreted by the mammalian vary. Estrne A naturally ccurring weak estrgen secreted by the mammalian vary. Glutathine A plypeptide prduced primarily in the liver; invlved in DNA synthesis and repair, prtein and prstaglandin synthesis, amin acid transprt, metablism f txins and carcingens, immune system functin, preventin f xidative cell damage, and enzyme activatin. Glycemic Index - A numerical value given t a carbhydrate-rich fd that is based n the average increase in bld glucse levels ccurring after the fd is eaten. Glycemic Lad - An index indicating the amunt f carbhydrate cntained in a specified serving f a particular fd. It is calculated by multiplying the fd's glycemic index by its carbhydrate cntent in grams and then dividing by 100. Insulin - Insulin is a hrmne prduced by the pancreas in the bdy that regulates the metablism f carbhydrates and fats, especially the cnversin f glucse t glycgen, which lwers the bdy s bld sugar level. Lignans - Phytestrgens that have a similar chemical structure t estradil and tamxifen; appear t ffer prtectin against breast cancer. Meta-analysis The prcess f using statistical methds t cmbine the results f different studies. Mutatin Abnrmal cell develpment. Nitrsamines Derivatives f nitrites that may be frmed in the stmach when nitrites cmbine with amines; carcingenic in animals. Phytnutrients Plant cmpunds that appear t have health-prtecting prperties. Plyphenls Phytnutrients that act as an antixidant; cmpunds that prtects the cells and bdy chemicals against damage caused by free radicals, reactive atms that cntribute t tissue damage in the bdy. Retinids Chemically related cmpunds with bilgical activity similar t that f retinl; related t vitamin A. Sex hrmne-binding glbulin (SHBG) A prtein in the bld that acts as a carrier fr andrgens and estradil; inhibits the estradil-induced prliferatin f breast cancer cells. 55

56 References 1. Byers T, Nestle M, McTiernan A, Dyle C, Currie-Williams A, Gansler T, et al. American Cancer Sciety 2001 Nutritin and Physical Activity Guidelines Advisry Cmmittee. American Cancer Sciety guidelines n nutritin and physical activity fr cancer preventin: Reducing the risk f cancer with healthy fd chices and physical activity. CA: Ca J Clin. 2002; 52(2): Link LB, Canchla AJ, Bernstein L, et al. Dietary patterns and breast cancer risk in the Califrnia Teachers Study chrt. Am J Clin Nutr. 2013;98(6): Demetriu CA, Hadjisavvas A, Lizidu MA, et al. The mediterranean dietary pattern and breast cancer risk in Greek-Cyprit wmen: a case-cntrl study. BMC Cancer. 2012;12: Gaudet MM, Brittn JA, Kabat GC, Steck-Sctt S, Eng SM, Teitelbaum SL, et al. Fruits, vegetables, and micrnutrients in relatin t breast cancer mdified by menpause and hrmne receptr status. Cancer Epidemil Bimarkers Prev. 2004;13(9): Wrld Cancer Research Fund. Fd, nutritin, physical activity, and the preventin f cancer: a glbal perspective. Washingtn, DC: American Institute fr Cancer Research, Ribli E, Nrat T. Epidemilgic evidence f the prtective effect f fruit and vegetables n cancer risk. Am J Clin Nutr. 2003;78(3 Suppl):559S-569S. 7. Hirse K, Matsu K, Iwata H, Tajima K. Dietary patterns and the risk f breast cancer in Japanese wmen. Cancer Sci. 2007;98(9): D MH, Lee SS, Kim JY, Jung PJ, Lee MH. Fruits, vegetables, sy fds and breast cancer in preand pstmenpausal Krean wmen: a case-cntrl study. Int J Vitam Nutr Res. 2007;77(2): Zhang S, Hunter DJ, Frman MR, Rsner BA, Speizer FE, Clditz GA, et al. Dietary cartenids and vitamins A, C, and E and risk f breast cancer. J Natl Cancer Inst. 1999;91(6): Freudenheim JL, Marshall JR, Vena JE, Laughlin, R, Brasure JR, Swansn MK, et al. Premenpausal breast cancer risk and intake f vegetables, fruits, and related nutrients. J Natl Cancer Inst. 1996;88(6): La Vecchia C, Altieri A, Tavani A. Vegetables, fruit, antixidants and cancer: a review f Italian studies. Eur J Nutr. 2001;40(6): Sant M, Allemani C, Sieri S, Krgh V, Menard S, Tagliabue E, et al. Salad vegetables dietary pattern prtects against HER-2- psitive breast cancer: a prspective Italian study. Int J Cancer. 2007;121(4): Pierce JP, Stefanick ML, Flatt SW, Natarajan L, Sternfeld B, Madlensky L, et al. Greater survival after breast cancer in physically active wmen with high vegetable-fruit intake regardless f besity. J Clin Oncl. 2007;25(17): de Lima FE, d Rsári Dias de Oliveira Latrre M, de Carvalh Csta MJ, Fisberg RM. Diet and cancer in Nrtheast Brazil: evaluatin f eating habits and fd grup cnsumptin in relatin t breast cancer. Cad Saude Publica. 2008;24(4): Bagliett L, Krishnan K, Severi G, et al. Dietary patterns and risk f breast cancer. Br J Cancer. 2011;104(3):

57 16. Ba P-P, Shu X-O, Zheng Y, et al. Fruit, vegetable, and animal fd intake and breast cancer risk by hrmne receptr status. Nutr Cancer. 2012;64(6): Butler LM, Wu AH, Wang R, Kh W-P, Yuan J-M, Yu MC. A vegetable-fruit-sy dietary pattern prtects against breast cancer amng pstmenpausal Singapre Chinese wmen. Am J Clin Nutr. 2010;91(4): Kruk J. Assciatin between Vegetable, Fruit and Carbhydrate Intake and Breast Cancer Risk in Relatin t Physical Activity. Asian Pac J Cancer Prev. 2014;15(11): Fung TT, Chiuve SE, Willett WC, Hankinsn SE, Hu FB, Hlmes MD. Intake f specific fruits and vegetables in relatin t risk f estrgen receptr-negative breast cancer amng pstmenpausal wmen. Breast Cancer Res Treat. 2013;138(3): Lima FEL de, Latrre M d RD de O, Csta MJ de C, Fisberg RM. Diet and cancer in Nrtheast Brazil: evaluatin f eating habits and fd grup cnsumptin in relatin t breast cancer. Cad Saude Publica. 2008;24(4): Liu X-O, Huang Y-B, Ga Y, et al. Assciatin between dietary factrs and breast cancer risk amng Chinese females: systematic review and meta-analysis. Asian Pac J Cancer Prev. 2014;15(3): Hui C, Qi X, Qianyng Z, Xiali P, Jundng Z, Mantian M. Flavnids, flavnid subclasses and breast cancer risk: a meta-analysis f epidemilgic studies. PLS One. 2013;8(1):e Masala G, Assedi M, Bendinelli B, et al. Fruit and vegetables cnsumptin and breast cancer risk: the EPIC Italy study. Breast Cancer Res Treat. 2012;132(3): Yu H, Hwang J-Y, R J, Kim J, Chang N. Vegetables, but nt pickled vegetables, are negatively assciated with the risk f breast cancer. Nutr Cancer. 2010;62(4): Zhang C-X, H SC, Chen Y-M, Fu J-H, Cheng S-Z, Lin F-Y. Greater vegetable and fruit intake is assciated with a lwer risk f breast cancer amng Chinese wmen. Int J Cancer. 2009;125(1): Sangrajrang S, Chaiwerawattana A, Plysawang P, Nklang K, Jamsri P, Smharnwng S. Obesity, diet and physical inactivity and risk f breast cancer in Thai wmen. Asian Pac J Cancer Prev. 2013;14(11): Gandini S, Merzenich H, Rbertsn C, Byle P. Meta-analysis f studies n breast cancer risk and diet: the rle f fruit and vegetable cnsumptin and the intake f assciated micrnutrients. Eur. J. Cancer 2000;36: Smith-Warner SA, Spiegelman D, Yaun SS, Adami HO, Beesn WL, van den Brandt PA, et al. Intake f fruits and vegetables and risk f breast cancer: a pled analysis f chrt studies. JAMA 2001;285: Shannn J, Ray R, Wu C, Nelsn Z, Ga DL, Li W, et al. Fd and btanical grupings and risk f breast cancer: a case- cntrl study in shanghai, china. Cancer Epidemil Bimarkers Prev. 2005;14(1): Miller JA, Lang JE, Ley M, et al. Human breast tissue dispsitin and biactivity f limnene in wmen with early-stage breast cancer. Cancer Prev Res (Phila). 2013;6(6): Lisswska J, Gaudet MM, Brintn LA, Peplnska B, Sherman M, Szeszenia-Dabrwska N, et al. Intake f fruits, and vegetables in relatin t breast cancer risk by hrmne receptr status. Breast Cancer Res Treat. 2008;107(1):

58 32. Bggs DA, Palmer JR, Wise LA, et al. Fruit and vegetable intake in relatin t risk f breast cancer in the Black Wmen s Health Study. Am J Epidemil. 2010;172(11): Fung TT, Hu FB, Hankinsn SE, Willett WC, Hlmes MD. Lw-carbhydrate diets, dietary appraches t stp hypertensin-style diets, and the risk f pstmenpausal breast cancer. Am J Epidemil. 2011;174(6): Rck CL, Flatt SW, Natarajan L, Thmsn CA, Bardwell WA, Newman VA, et al. Plasma cartenids and recurrence-free survival in wmen with a histry f breast cancer. J Clin Oncl. 2005;23: Pierce JP, Natarajan L, Caan BJ, Parker BA, Greenberg ER, Flatt SW, et al. Influence f a diet very high in vegetables, fruit, and fiber and lw in fat n prgnsis fllwing treatment fr breast cancer: the Wmen s Healthy Eating and Living (WHEL) randmized trial. JAMA. 2007;298(3): McEligt AJ, Largent J, Zigas A, Peel D, Antn-Culver H. Dietary fat, fiber, vegetable, and micrnutrients are assciated with verall survival in pstmenpausal wmen diagnsed with breast cancer. Nutr Cancer. 2006;55(2): Nrat T, Dssus L, Rinaldi S, Overvad K, Grønbaek H, Tjønneland A, et al. Diet, serum insulin-like grwth factr-i and IGF- binding prtein-3 in Eurpean wmen. Eur J Clin Nutr. 2007;61(1): It Y, Gajalakshmi KC, Sasaki R, Suzuki K, Shanta V. A study n serum cartenid levels in breast cancer patients f Indian wmen in Chennai (Madras), India. J Epidemil. 1999;9(5): Tibaduiza EC, Fleet JC, Russell RM, Krinsky NI. Excentric cleavage prducts f beta-cartene inhibit estrgen receptr psitive and negative breast tumr cell grwth in vitr and inhibit activatr prtein-1-mediated transcriptinal activatin. J Nutr. 2002;132(6): Huang JP, Zhang M, Hlman CD, Xie X. Dietary cartenids and risk f breast cancer in Chinese wmen. Asia Pac J Clin Nutr. 2007;16 Suppl 1: Cui Y, Shikany JM, Liu S, Shagufta Y, Rhan TE. Selected antixidants and risk f hrmne receptr-defined invasive breast cancers amng pstmenpausal wmen in the Wmen s Health Initiative Observatinal Study. Am J Clin Nutr. 2008;87(4): Nkndjck A, Ghardirian P. Intake f specific cartenids and essential fatty acids and breast cancer risk in Mntreal, Canada. Am J Clin Nutr. 2004;79(5): Kim MK, Park TG, Gng G, Ahn SH. Breast cancer, serum antixidant vitamins, and p53 prtein verexpressin. Nutr Cancer 2002;43(2): Sat R, Helzlsuer KJ, Alberg AJ, Hffman SC, Nrkus EP, Cmstck GW. Prspective study f cartenids, tcpherls, and retinid cncentratins and the risk f breast cancer. Cancer Epidemil Bimarkers Prev. 2002;11(5): Ching S, Ingram D, Hahnel R, Beilby J, Rssi E. Serum levels f micrnutrients, antixidants and ttal antixidant status predict risk f breast cancer in a case cntrl study. J Nutr. 2002;132(2): Tnil P, Van Kappel AL, Akhemedkhanv A, Ferrari P, Kat I, Shre RE, et al. Serum cartenids and breast cancer. Am J Epidemil. 2001;153(12): Aune D, Chan DSM, Vieira AR, et al. Dietary cmpared with bld cncentratins f cartenids and breast cancer risk: a systematic review and meta-analysis f prspective studies. Am J Clin Nutr. 2012;96(2):

59 48. Eliassen AH, Hendricksn SJ, Brintn LA, et al. Circulating cartenids and risk f breast cancer: pled analysis f eight prspective studies. J Natl Cancer Inst. 2012;104(24): Puchieu C, Galan P, Ducrs V, Latin-Martel P, Hercberg S, Tuvier M. Plasma cartenids and retinl and verall and breast cancer risk: a nested case-cntrl study. Nutr Cancer. 2014;66(6): Li Z, Wang Y, M B. [The effects f cartenids n the prliferatin f human breast cancer cell and gene expressin f bcl-2][article in Chinese] Zhnghua Yu Fang Yi Xue Za Zhi 2002;36(4): Prakash P, Russell RM, Krinsky NI. In vitr inhibitin f prliferatin f estrgen-dependent and estrgen-independent human breast cancer cells treated with cartenids r retinids. J Nutr. 2001;131(5): Glria NF, Sares N, Brand C, Oliveira FL, Brjevic R, Tedr AJ. Lycpene and beta-cartene induce cell-cycle arrest and apptsis in human breast cancer cell lines. Anticancer Res. 2014;34(3): Li Z, Hu CY, M BQ, Xu JD, Zha Y. Effect f beta-cartene n gene expressin f breast cancer cells] [Article in Chinese] Ai Zheng 2003;22(4): Negri E, La Vecchia C, Franceschi S, D Avanz B, Talamini R, Parpinel M, et al. Intake f selected micrnutrients and the risk f breast cancer. Int J Cancer 1996;65(2): Schuurman AG, Gldbhm RA, Brants HA, van den Brandt PA. A prspective chrt study n intake f retinl, vitamins C and E, and cartenids and prstate cancer risk (Netherlands). Cancer Causes Cntrl 2002;13(6): Hennekens CH, Buring JE, Mansn JE, Stampfer M, Rsner B, Ck NR, et al. Lack f effect f lng-term supplementatin with beta cartene n the incidence f malignant neplasms and cardivascular disease. New Engl J Med. 1996;334(18): Wang L, Li B, Pan M-X, M X-F, Chen Y-M, Zhang C-X. Specific cartenid intake is inversely assciated with the risk f breast cancer amng Chinese wmen. Br J Nutr. 2014;111(9): Zhang X, Spiegelman D, Bagliett L, et al. Cartenid intakes and risk f breast cancer defined by estrgen receptr and prgesterne receptr status: a pled analysis f 18 prspective chrt studies. Am J Clin Nutr. 2012;95(3): Abdull Razis AF, Nr NM. Cruciferus vegetables: dietary phytchemicals fr cancer preventin. Asian Pac J Cancer Prev. 2013;14(3): Suzuki R, Iwasaki M, Hara A, et al. Fruit and vegetable intake and breast cancer risk defined by estrgen and prgesterne receptr status: the Japan Public Health Center-based Prspective Study. Cancer Causes Cntrl. 2013;24(12): Ambrsne CB, McCann SE, Freudenheim JL, Marshall JR, Zhang Y, Shields PG. Breast cancer risk in premenpausal wmen is inversely assciated with cnsumptin f brccli, a surce f isthicyanates, but is nt mdified by GST gentype. J Nutr. 2004;134(5): Terry P, Wlk A, Perssn I, Magnussn C. Brassica vegetables and breast cancer risk. JAMA. 2001;285(23): Brandi G, Schiavan GF, Zaffarni N, De Marc C, Paiardini M, Cervasi B, et al. Mechanisms f actin and antiprliferative prperties f Brassica leracea juice in human breast cancer cell lines. J Nutr. 2005;135(6):

60 64. [N authrs nted] Change in Diet at Any Age May Help Prtect Against Breast Cancer (Abstract #3697. American Assciatin fr Cancer Research s 4th annual Frntiers in Cancer Preventin Research meeting. Nv Lee SA, Fwke JH, Lu W, Ye C, Zheng Y, Cai Q, et al. Cruciferus vegetables, the GSTP1 Ile105Val genetic plymrphism, and breast cancer risk. Am J Clin Nutr. 2008;87(3): Liu X, Lv K. Cruciferus vegetables intake is inversely assciated with risk f breast cancer: a metaanalysis. Breast. 2013;22(3): Bradlw HL, Sepkvic DW, Telang NT, Osbrne MP. Multifunctinal aspects f the actin f indle- 3-carbinl as an antitumr agent. Ann N Y Acad Sci. 1999;889: Fwke JH, Lngcpe C, Hebert JR. Brassica vegetable cnsumptin shifts estrgen metablism in healthy pstmenpausal wmen. Cancer Epidemil Bimarkers Prev. 2000;9(8): Kim S-H, Sehrawat A, Singh S V. Dietary chempreventative benzyl isthicyanate inhibits breast cancer stem cells in vitr and in viv. Cancer Prev Res (Phila). 2013;6(8): Jacksn SJ, Singletary KW. Sulfraphane: a naturally ccurring mammary carcinma mittic inhibitr, which disrupts tubulin plymerizatin. Carcingenesis. 2004;25(2): Tseng E, Sctt-Ramsay EA, Mrris ME. Dietary Organic Isthicyanates Are Cyttxic in Human Breast Cancer MCF-7 and Mammary Epithelial MCF-12A Cell Lines. Exp Bil Med (Maywd). 2004;229(8): J EH, Kim SH, Ahn NS, Park JS, Hwang JW, Lee YS, et al. Efficacy f sulfraphane is mediated by p38 MAP kinase and caspase-7 activatins in ER-psitive and COX-2-expressed human breast cancer cells. Eur J Cancer Prev. 2007;16(6): Pledgie-Tracy A, Sblewski MD, Davidsn NE. Sulfraphane induces cell type-specific apptsis in human breast cancer cell lines. Ml Cancer Ther. 2007;6(3): Chatterji U, Riby JE, Taniguchi T, Bjeldanes EL, Bjeldanes LF, Firestne GL. Indle-3-carbinl stimulates transcriptin f the interfern gamma receptr 1 gene and augments interfern respnsiveness in human breast cancer cells. Carcingenesis 2004;25(7): Wu HT, Lin SH, Chen YH. Inhibitin f Cell Prliferatin and in Vitr Markers f Angigenesis by Indle-3-carbinl, a Majr Indle Metablite Present in Cruciferus Vegetables. J Agric Fd Chem. 2005;53(13): Ge X, Fares FA, Yannai S. Inductin f apptsis in MCF-7 cells by indl-3-carbinl is independent f p53 and bax. Anticancer Res. 1999;19(4B): Telang NT, Katdare M, Bradlw HL, Osbrne MP, Fishman J. Inhibitin f prliferatin and mdulatin f estradil metablism: nvel mechanisms fr breast cancer preventin by the phytchemical indle-3-carbinl. Prc Sc Exp Bil Med. 1997;216(2): Cver CM, Hsieh SJ, Cram EJ, Hng C, Riby JE, Bjeldanes LF, et al. Indle-3-carbinl and tamxifen cperate t arrest the cell cycle f MCF-7 human breast cancer cells. Cancer Res. 1999;59(6): Brignall MS. Preventin and treatment f cancer with indle-3-carbinl. Altern Med Rev. 2001;6(6): [N authrs listed] Calcium-D-glucarate. Altern Med Rev. 2002;7(4):

61 81. van Elswijk DA, Schbel UP, Lansky EP, Irth H, van der Greef J. Rapid dereplicatin f estrgenic cmpunds in pmegranate (Punica granatum) using n-line bichemical detectin cupled t mass spectrmetry. Phytchemistry 2004;65(2): Ti M, Band H, Ramachandran C, Melnick SJ, Imai A, Fife RS, et al. Preliminary studies n the anti-angigenic ptential f pmegranate fractins in vitr and in viv. Angigenesis 2003;6(2): Kim ND, Mehta R, Yu W, Neeman I, Livney T, Amichay A, et al. Chempreventive and adjuvant therapeutic ptential f pmegranate (Punica granatum) fr human breast cancer. Breast Cancer Res Treat. 2002;71(3): Aqil F, Munagala R, Vadhanam M V, et al. Anti-prliferative activity and prtectin against xidative DNA damage by punicalagin islated frm pmegranate husk. Fd Res Int. 2012;49(1): Rcha A, Wang L, Penichet M, Martins-Green M. Pmegranate juice and specific cmpnents inhibit cell and mlecular prcesses critical fr metastasis f breast cancer. Breast Cancer Res Treat. 2012;136(3): Mehta R, Lansky EP. Breast cancer chempreventive prperties f pmegranate (Punica granatum) fruit extracts in a muse mammary rgan culture. Eur J Cancer Prev. 2004;13(4): Dai Z, Nair V, Khan M, Cilin HP. Pmegranate extract inhibits the prliferatin and viability f MMTV-Wnt-1 muse mammary cancer stem cells in vitr. Oncl Rep. 2010;24(4): Dikmen M, Ozturk N, Ozturk Y. The antixidant ptency f Punica granatum L. Fruit peel reduces cell prliferatin and induces apptsis n breast cancer. J Med Fd. 2011;14(12): Shirde AB, Kvvuru P, Chittur S V, Henning SM, Heber D, Reliene R. Antiprliferative effects f pmegranate extract in MCF-7 breast cancer cells are assciated with reduced DNA repair gene expressin and inductin f duble strand breaks. Ml Carcing. 2014;53(6): Lmbardi-Bccia G, Lucarini M, Lanzi S, Aguzzi A, Cappellni M. Nutrients and antixidant mlecules in yellw plums (Prunus dmestica L.) frm cnventinal and rganic prductins: a cmparative study. J Agric Fd Chem. 2004;52(1): Grinder-Pedersen L, Rasmussen SE, Bugel S, Jrgensen LV, Dragsted LO, et al. Effect f diets based n fds frm cnventinal versus rganic prductin n intake and excretin f flavnids and markers f antixidative defense in humans. J Agric Fd Chem. 2003;51(19): Asami DK, Hng YJ, Barrett DM, Mitchell AE. Cmparisn f the ttal phenlic and ascrbic acid cntent f freeze-dried and air-dried marinberry, strawberry, and crn grwn using cnventinal, rganic, and sustainable agricultural practices. J Agric Fd Chem. 2003;51(5): Baxter GJ, Graham AB, Lawrence JR, Wiles D, Patersn JR. Salicylic acid in sups prepared frm rganically and nn- rganically grwn vegetables. Eur J Nutr. 2001;40(6): Ferreres F, Valenta P, Llrach R, Pinheir C, Cards L, Pereira JA, et al. Phenlic cmpunds in external leaves f trnchuda cabbage (Brassica leracea L. var. cstata DC). J Agric Fd Chem. 2005;53(8): Kazimierczak R, Hallmann E, Lipwski J, et al. Beetrt (Beta vulgaris L.) and naturally fermented beetrt juices frm rganic and cnventinal prductin: metablmics, antixidant levels and anticancer activity. J Sci Fd Agric Olssn ME, Anderssn CS, Oredssn S, Berglund RH, Gustavssn K-E. Antixidant levels and inhibitin f cancer cell prliferatin in vitr by extracts frm rganically and cnventinally cultivated strawberries. J Agric Fd Chem. 2006;54(4):

62 97. Li JY, Li H, Ta P, Lei FM. [Serum rganchlrines pesticides level f nn-ccupatinal expsure wmen and risk f breast cancer:a case-cntrl study]. [Article in Chinese] Wei Sheng Yan Jiu. 2006;35(4): Wng PS, Matsumura F. Prmtin f breast cancer by beta-hexachlrcyclhexane in MCF10AT1 cells and MMTV-neu mice. BMC Cancer. 2007;7: Khanjani N, Hving JL, Frbes AB, Sim MR. Systematic review and meta-analysis f cycldiene insecticides and breast cancer. J Envirn Sci Health C Envirn Carcing Ectxicl Rev. 2007;25(1): Teitelbaum SL, Gammn MD, Brittn JA, Neugut AI, Levin B, Stellman SD. Reprted residential pesticide use and breast cancer risk n Lng Island, New Yrk. Am J Epidemil. 2007;165(6): Muñz-de-Tr M, Durand M, Beldménic PM, Beldménic HR, Kass L, García SR, et al. Estrgenic micrenvirnment generated by rganchlrine residues in adipse mammary tissue mdulates bimarker expressin in ERalpha-psitive breast carcinmas. Breast Cancer Res. 2006;8(4):R Harris PJ, Rbertn AM, Watsn ME, Triggs CM, Fergusn LR. The effects f sluble-fiber plysaccharides n the adsrptin f a hydrphbic carcingen t an insluble dietary fiber. Nutr Cancer 1993;19(1): Slavin JL. Mechanisms fr the impact f whle grain fds n cancer risk. J Am Cll Nutr. 2000;19(3 Suppl):300S-307S Slavin J. Why whle grains are prtective: bilgical mechanisms. Prc Nutr Sc. 2003;62(1): Stll BA. Can supplementary dietary fibre suppress breast cancer grwth? Br J Cancer 1996;73(5): Bagga D, Ashley JM, Geffrey SP, Wang HJ, Barnard RJ, Krenman S, et al. Effects f a very lw fat, high fiber diet n serum hrmnes and menstrual functin. Implicatins fr breast cancer preventin. Cancer 1995;76(12): Rck CL, Flatt SW, Thmsn CA, Stefanick ML, Newman VA, Jnes LA, et al. Effects f a highfiber, lw-fat diet interventin n serum cncentratins f reprductive sterid hrmnes in wmen with a histry f breast cancer. J Clin Oncl. 2004;22(12): Wayne SJ, Neuhuser ML, Ulrich CM, Kprwski C, Baumgartner KB, Baumgartner RN, et al. Dietary fiber is assciated with serum sex hrmnes and insulin-related peptides in pstmenpausal breast cancer survivrs. Breast Cancer Res Treat Dec Gldin BR, Adlercreutz H, Grbach SL, Warram JH, Dwyer JT, Swensn L, et al. Estrgen excretin patterns and plasma levels in vegetarian and mnivrus wmen. N Engl J Med. 1982;307: Villaseñr A, Ambs A, Ballard-Barbash R, et al. Dietary fiber is assciated with circulating cncentratins f C-reactive prtein in breast cancer survivrs: the HEAL study. Breast Cancer Res Treat. 2011;129(2): Dng J-Y, He K, Wang P, Qin L-Q. Dietary fiber intake and risk f breast cancer: a meta-analysis f prspective chrt studies. Am J Clin Nutr. 2011;94(3):

63 112. Ferrari P, Rinaldi S, Jenab M, et al. Dietary fiber intake and risk f hrmnal receptr-defined breast cancer in the Eurpean Prspective Investigatin int Cancer and Nutritin study. Am J Clin Nutr. 2013;97(2): Li Q, Hlfrd TR, Zhang Y, et al. Dietary fiber intake and risk f breast cancer by menpausal and estrgen receptr status. Eur J Nutr. 2013;52(1): Sulaiman S, Shahril MR, Wafa SW, Shaharudin SH, Hussin SNAS. Dietary carbhydrate, fiber and sugar and risk f breast cancer accrding t menpausal status in malaysia. Asian Pac J Cancer Prev. 2014;15(14): Zhang C-X, H SC, Cheng S-Z, Chen Y-M, Fu J-H, Lin F-Y. Effect f dietary fiber intake n breast cancer risk accrding t estrgen and prgesterne receptr status. Eur J Clin Nutr. 2011;65(8): Cade JE, Burley VJ, Greenwd DC; UK Wmen s Chrt Study Steering Grup. Dietary fibre and risk f breast cancer in the UK Wmen s Chrt Study. Int J Epidemil. 2007;36(2): Mattissn I, Wirfalt E, Jhanssn U, Gullberg B, Olssn H, Berglund G. Intakes f plant fds, fibre and fat and risk f breast cancer--a prspective study in the Malmà Diet and Cancer chrt. Br J Cancer 2004;90(1): Terry P, Jain M, Miller AB, Hwe GR, Rhan TE. N assciatin amng ttal dietary fiber, fiber fractins, and risk f breast cancer. Cancer Epidemil Bimarkers Prev. 2002;11(11): Ch E, Spiegelman D, Hunter DJ, Chen WY, Clditz GA, Willett WC. Premenpausal dietary carbhydrate, glycemic index, glycemic lad, and fiber in relatin t risk f breast cancer. Cancer Epidemil Bimarkers Prev. 2003;12(11 Pt 1): Hwe GR, Hirhata T, Hislp TG, Iscvich JM, Yuan JM, Katsuyanni K, et al. Dietary factrs and risk f breast cancer: cmbined analysis f 12 case-cntrl studies. J Natl Cancer Inst. 1990;82: De Stefani E, Crrea P, Rnc A, Mendilaharsu M, Guidbn M, Dene-Pellegrini H. Dietary fiber and risk f breast cancer: a case-cntrl study in Uruguay. Nutr Cancer 1997;28: La Vecchia C, Ferrarni M, Franceschi S, Mezzetti M, Decarli A, Negri E. Fibers and breast cancer risk. Nutr Cancer 1997;28: Challier B, Perarnau JM, Viel JF. Garlic, nin and cereal fibre as prtective factrs fr breast cancer: a French case-cntrl study. Eur J Epidemil. 1998;14: Rhan TE, Hwe GR, Friedenreich CM, Jain M, Miller AB. Dietary fiber, vitamins A, C, and E, and risk f breast cancer: a chrt study. Cancer Causes Cntrl 1993;4: Aune D, Chan DSM, Greenwd DC, et al. Dietary fiber and breast cancer risk: a systematic review and meta-analysis f prspective studies. Ann Oncl. 2012;23(6): Adebamw CA, Ch E, Sampsn L, Katan MB, Spiegelman D, Willett WC, et al. Dietary flavnls and flavnl-rich fds intake and the risk f breast cancer. Int J Cancer 2005;114(4): Muti P, Quattrin T, Grant BJ, Krgh V, Micheli A, Schunemann HJ, et al. Fasting glucse is a risk factr fr breast cancer: a prspective study. Cancer Epidemil Bimarkers Prev. 2002;11(11):

64 128. Hadsell DL, Bnnette SG. IGF and insulin actin in the mammary gland: lessns frm transgenic and knckut mdels. J Mammary Gland Bil Neplasia 2000;5(1): McCance KL, Jnes RE. Estrgen and insulin crsstalk: breast cancer risk implicatins. Nurse Pract. 2003;28(5): Shi R, Yu H, McLarty J, Glass J. IGF-I and breast cancer: a meta-analysis. Int J Cancer 2004;111(3): Yu H, Rhan T. Rle f the insulin-like grwth factr family in cancer develpment and prgressin. J Natl Cancer Inst. 2000; 92: Muti P. The rle f endgenus hrmnes in the etilgy and preventin f breast cancer: the epidemilgical evidence. Ann N Y Acad Sci. 2004;1028: Osbrne CK, Clemmns DR, Arteaga CL. Regulatin f breast cancer grwth by insulin-like grwth factrs. J Sterid Bichem Ml Bil. 1990;37(6): Lee AV, Jacksn JG, Gch JL, Hilsenbeck SG, Crnad-Heinshn E, Osbrne CK, et al. Enhancement f insulin-like grwth factr signaling in human breast cancer: estrgen regulatin f insulin receptr substrate-1 expressin in vitr and in viv. Ml Endcrinl. 1999;13: Malin A, Dai Q, Yu H, Shu XO, Jin F, Ga YT. Evaluatin f the synergistic effect f insulin resistance and insulin-like grwth factrs n the risk f breast carcinma. Cancer 2004;100(4): Duggan C, Wang C-Y, Neuhuser ML, et al. Assciatins f insulin-like grwth factr and insulinlike grwth factr binding prtein-3 with mrtality in wmen with breast cancer. Int J Cancer. 2013;132(5): Hankinsn SE, Willett WC, Clditz GA, Hunter DJ, Michaud DS, Der B, et al. Circulating cncentratins f insulin-like grwth factr-i and risk f breast cancer. Lancet 1998;351(9113): Kaaks R, Jhnsn T, Tikk K, et al. Insulin-like grwth factr I and risk f breast cancer by age and hrmne receptr status-a prspective study within the EPIC chrt. Int J Cancer. 2014;134(11): Schernhammer ES, Hlly JM, Pllak MN, Hankinsn SE. Circulating levels f insulin-like grwth factrs, their binding prteins, and breast cancer risk. Cancer Epidemil Bimarkers Prev. 2005;14(3): Pllak M, Cnstantin J, Plychrnaks C, Blauer SA, Guyda H, Redmnd C, et al. Effect f tamxifen n serum insulinlike grwth factr I levels in stage I breast cancer patients. J Natl Cancer Inst. 1990;82(21): Eliassen AH, Twrger SS, Mantzrs CS, Pllak MN, Hankinsn SE. Circulating insulin and c-peptide levels and risk f breast cancer amng predminately premenpausal wmen. Cancer Epidemil Bimarkers Prev. 2007;16(1): Lawlr DA, Smith GD, Ebrahim S. Hyperinsulinaemia and increased risk f breast cancer: findings frm the British Wmen s Heart and Health Study. Cancer Causes Cntrl 2004;15(3): Stll BA. Bilgical mechanisms in breast cancer invasiveness: relevance t preventive interventins. Eur J Cancer Prev. 2000;9(2):

65 144. Brugian MJ, Sheps SB, Kim-Sing C, Van Patten C, Ptter JD, Dunn B, et al. Insulin, macrnutrient intake, and physical activity: are ptential indicatrs f insulin resistance assciated with mrtality frm breast cancer? Cancer Epidemil Bimarkers Prev. 2004;13(7): Gnullu G, Ersy C, Ersy A, Evrensel T, Basturk B, Kurt E, et al. Relatin between insulin resistance and serum cncentratins f IL-6 and TNF-alpha in verweight r bese wmen with early stage breast cancer. Cytkine 2005;31(4): Gdwin PJ, Ennis M, Pritchard KI, Trudeau ME, K J, Madarnas Y, et al. Fasting insulin and utcme in early-stage breast cancer: results f a prspective chrt study. J Clin Oncl. 2002;20: Rmieu I, Lazcan-Pnce E, Sanchec-Zamran LM, Wallett W, Hernandez-Avila M. Carbhydrates and the risk f breast cancer amng Mexican wmen. Cancer Epidemil Bimarkers Prev. 2004;13(8): Tavani A, Girdan L, Gallus S, Talamini R, Franceschi S, Giacsa A, et al. Cnsumptin f sweet fds and breast cancer risk in Italy. Ann Oncl Oct Duchaine CS, Dumas I, Diri C. Cnsumptin f sweet fds and mammgraphic breast density: a crss-sectinal study. BMC Public Health. 2014;14: Bradshaw PT, Sagiv SK, Kabat GC, et al. Cnsumptin f sweet fds and breast cancer risk: a case-cntrl study f wmen n Lng Island, New Yrk. Cancer Causes Cntrl. 2009;20(8): Cntier P, Berrin F, Tagliabue G, et al. Fasting bld glucse and lng-term prgnsis f nnmetastatic breast cancer: a chrt study. Breast Cancer Res Treat. 2013;138(3): Miniczzi P, Berrin F, Sebastiani F, et al. High fasting bld glucse and besity significantly and independently increase risk f breast cancer death in hrmne receptr-psitive disease. Eur J Cancer. 2013;49(18): Tavani A, Girdan L, Gallus S, Talamini R, Franceschi S, Giacsa A, et al. Cnsumptin f sweet fds and breast cancer risk in Italy. Ann Oncl. 2006;17(2): Sieri S, Pala V, Brighenti F, Pellegrini N, Muti P, Micheli A, et al. Dietary glycemic index, glycemic lad, and the risk f breast cancer in an Italian prspective chrt study. Am J Clin Nutr. 2007;86(4): Lajus M, Butrn-Ruault MC, Fabre A, Clavel-Chapeln F, Rmieu I. Carbhydrate intake, glycemic index, glycemic lad, and risk f pstmenpausal breast cancer in a prspective study f French wmen. Am J Clin Nutr. 2008;87(5): Barclay AW, Petcz P, McMillan-Price J, Fld VM, Prvan T, Mitchell P, et al. Glycemic index, glycemic lad, and chrnic disease risk--a meta-analysis f bservatinal studies. Am J Clin Nutr. 2008;87(3): Larssn SC, Bergkvist L, Wlk A. Glycemic lad, glycemic index and breast cancer risk in a prspective chrt f Swedish wmen. Int J Cancer. 2009;125(1): Sieri S, Pala V, Brighenti F, et al. High glycemic diet and breast cancer ccurrence in the Italian EPIC chrt. Nutr Metab Cardivasc Dis. 2013;23(7): Chlebwski RT, Blackburn GL, Thmsn CA, Nixn DW, Shapir A, Hy MK, et al. Dietary fat reductin and breast cancer utcme: interim efficacy results frm the Wmen s Interventin Nutritin Study. J Natl Cancer Inst. 2006;98(24):

66 160. Schulz M, Hffmann K, Weikert C, Nöthlings U, Schulze MB, Being H. Identificatin f a dietary pattern characterized by high-fat fd chices assciated with increased risk f breast cancer: the Eurpean Prspective Investigatin int Cancer and Nutritin (EPIC)-Ptsdam Study. Br J Nutr Apr 1: Farvid MS, Ch E, Chen WY, Eliassen AH, Willett WC. Premenpausal dietary fat in relatin t pre- and pst-menpausal breast cancer. Breast Cancer Res Treat. 2014;145(1): Sieri S, Chidini P, Agnli C, et al. Dietary fat intake and develpment f specific breast cancer subtypes. J Natl Cancer Inst. 2014;106(5) Drgan JF, Hunsberger SA, McMahn RP, Kwitervich PO Jr, Lauer RM, Van Hrn L, et al. Diet and sex hrmnes in girls: findings frm a randmized cntrlled clinical trial. J Natl Cancer Inst. 2003;95(2): Nthlings U, Wilkens LR, Murphy SP, Hankin JH, Hendersn BE, Klnel LN. Meat and fat intake as risk factrs fr pancreatic cancer: the multiethnic chrt study. J Natl Cancer Inst. 2005;97(19): Qiu JL, Chen K, Zheng JN, Wang JY, Zhang LJ, Sui LM. Nutritinal factrs and gastric cancer in Zhushan Islands, China. Wrld J Gastrenterl. 2005;11(28): Gnzalez CA, Navarr C, Martinez C, Quirs JR, Drrnsr M, Barricarte A, et al. [The Eurpean prspective investigatin abut cancer and nutritin (EPIC)] [Article in Spanish] Rev Esp Salud Publica 2004;78(2): Althaimeen A, Ezzat A, Mhamed G, Muammar T, Al-Maduj A. Dietary fat and breast cancer in Saudi Arabia: a case- cntrl study. East Mediterr Health J. 2004;10(6): Jrdan I, Hebestreit A, Swai B, Krawinkel MB. Dietary patterns and breast cancer risk amng wmen in nrthern Tanzania: a case-cntrl study. Eur J Nutr. 2013;52(3): Krenke CH, Kwan ML, Sweeney C, Castill A, Caan BJ. High- and lw-fat dairy intake, recurrence, and mrtality after breast cancer diagnsis. J Natl Cancer Inst. 2013;105(9): Makarem N, Chandran U, Bandera E V, Parekh N. Dietary fat in breast cancer survival. Annu Rev Nutr. 2013;33: Saadatian-Elahi M, Nrat T, Gudable J, Ribli E. Bimarkers f dietary fatty acid intake and the risk f breast cancer: a meta-analysis. Int J Cancer 2004;111(4): Byd NF, Stne J, Vgt KN, Cnnelly BS, Martin LJ, Minkin S. Dietary fat and breast cancer risk revisited: a meta-analysis f the published literature. Br J Cancer 2003;89(9): Gag-Dminguez M, Yuan JM, Sun CL, Lee HP, Yu MC. Oppsing effects f dietary n-3 and n-6 fatty acids n mammary carcingenesis: The Singapre Chinese Health Study. Br J Cancer 2003;89(9): Hlmes MD, Hunter DJ, Clditz GA, Stampher MJ, Hankinsn SE, Speizer FE, et al. Assciatin f dietary intake f fat and fatty acids with risk f breast cancer. JAMA 1999;281(10): Wlk A, Bergstrm R, Hunter D, Willett W, Ljung H, Hlmberg L, et al. A prspective study f assciatin f mnunsaturated fat and ther types f fat with risk f breast cancer. Arch Intern Med. 1998;158(1): Bakker N, Van t Veer P, Zck PL. Adipse fatty acids and cancers f the breast, prstate and cln: an eclgical study. EURAMIC Study Grup. Int J Cancer 1997;72(4):

67 177. Slattery ML, Bensn J, Ma KN, Schaffer D, Ptter JD. Trans-fatty acids and cln cancer. Nutr Cancer 2001;39(2): Vrrips LE, Brants HA, Kardinaal AF, Kiddink GJ, van den Brandt PA, Gldbhm RA. Intake f cnjugated linleic acid, fat, and ther fatty acids in relatin t pstmenpausal breast cancer: the Netherlands Chrt Study n Diet and Cancer. Am J Clin Nutr. 2002;76(4): Chajès V, Thiébaut AC, Rtival M, Gauthier E, Maillard V, Butrn-Ruault MC, et al. Assciatin between serum trans- mnunsaturated fatty acids and breast cancer risk in the E3N-EPIC Study. Am J Epidemil. 2008;167(11): Rissanen H, Knekt P, Jarvinen R, Salminen I, Hakulinen T. Serum fatty acids and breast cancer incidence. Nutr Cancer 2003;45(2): Khlmeier L, Simnsen N, van t Veer P, Strain JJ, Martin-Mren JM, Marglin B, et al. Adipse tissue trans fatty acids and breast cancer in the Eurpean Cmmunity Multicenter Study n Antixidants, Mycardial Infarctin, and Breast Cancer. Cancer Epidemil Bimarkers Prev. 1997;6(9): Bartsch H, Nair J, Owen RW. Dietary plyunsaturated fatty acids and cancers f the breast and clrectum: emerging evidence fr their rle as risk mdifiers. Carcingenesis 1999;20(12): Slanas M, Hurtad A, Csta I, Mral R, Menendez JA, Clmer R, et al. Effects f a high live il diet n the clinical behavir and histpathlgical features f rat DMBA-induced mammary tumrs cmpared with a high crn il diet. Int J Oncl. 2002;21(4): García-Segvia P, Sánchez-Villegas A, Dreste J, Santana F, Serra-Majem L. Olive il cnsumptin and risk f breast cancer in the Canary Islands: a ppulatin-based case-cntrl study. Public Health Nutr. 2006;9(1A): Martin-Mren JM, Willett, WC, Grgj L, Banegas JR, Rdriguez-Artalej F, Fernandez- Rdriguez JC, et al. Dietary fat, live il intake and breast cancer risk. Int J Cancer 1994;58(6): la Vecchia C, Negri E, Franceschi S, Decarli A, Giacsa A, Lipwrth L. Olive il, ther dietary fats, and the risk f breast cancer (Italy). Cancer Causes Cntrl 1995;6(6): Trichpulu A, Katsuyanni K, Stuver S, Tzala L, Gnardellis C, Rimm E, et al. Cnsumptin f live il and specific fd grups in relatin t breast cancer risk in Greece. J Natl Cancer Inst. 1995;87(2): Wakai K, Tamakshi K, Date C, Fukui M, Suzuki S, Lin Y, et al. Dietary intakes f fat and fatty acids and risk f breast cancer: a prspective study in Japan. Cancer Sci. 2005;96(9): Caygill CP, Charlett A, Hill MJ. Fat, fish, fish il and cancer. Br J Cancer 1996;74(1): Maillard V, Bugnux P, Ferrari P, Jurdan ML, Pinault M, Lavillnniere F, et al. N-3 and N-6 fatty acids in breast adipse tissue and relative risk f breast cancer in a case-cntrl study in Turs, France. Int J Cancer 2002;98(1): Psaltpulu T, Ksti RI, Haidpuls D, Dimpuls M, Panagitaks DB. Olive il intake is inversely related t cancer prevalence: a systematic review and a meta-analysis f 13,800 patients and 23,340 cntrls in 19 bservatinal studies. Lipids Health Dis. 2011;10: Pelucchi C, Bsetti C, Negri E, Lipwrth L, La Vecchia C. Olive il and cancer risk: an update f epidemilgical findings thrugh Curr Pharm Des. 2011;17(8):

68 193. Buckland G, Travier N, Agud A, et al. Olive il intake and breast cancer risk in the Mediterranean cuntries f the Eurpean Prspective Investigatin int Cancer and Nutritin study. Int J Cancer. 2012;131(10): Escrich E, Slanas M, Mral R. Olive il and ther dietary lipids in breast cancer. Cancer Treat Res. 2014;159: Hassan ZK, Elamin MH, Daghestani MH, et al. Oleurpein induces anti-metastatic effects in breast cancer. Asian Pac J Cancer Prev. 2012;13(9): Hassan ZK, Elamin MH, Omer SA, et al. Oleurpein induces apptsis via the p53 pathway in breast cancer cells. Asian Pac J Cancer Prev. 2014;14(11): Bagga D, Anders KH, Wang HJ, Glaspy JA. Lng-chain n-3-t-n-6 plyunsaturated fatty acid ratis in breast adipse tissue frm wmen with and withut breast cancer. Nutr Cancer 2002;42(2): Hardman WE. (n-3) fatty acids and cancer therapy. J Nutr. 2004;134(12 Suppl):3427S-3430S Kuriki K, Hirse K, Wakai K, Matsu K, It H, Suzuki T, Hiraki A, Sait T, Iwata H, Tatematsu M, Tajima K. Breast cancer risk and erythrcyte cmpsitins f n-3 highly unsaturated fatty acids in Japanese. Int J Cancer. 2007;121(2): Shannn J, King IB, Mshfsky R, Lampe JW, Ga DL, Ray RM, Thmas DB. Erythrcyte fatty acids and breast cancer risk: a case-cntrl study in Shanghai, China. Am J Clin Nutr. 2007;85(4): Chung H, Lee YS, Mayral R, et al. Omega-3 fatty acids reduce besity-induced tumr prgressin independent f GPR120 in a muse mdel f pstmenpausal breast cancer. Oncgene. 2014; Sep Sczaniecka AK, Brasky TM, Lampe JW, Pattersn RE, White E. Dietary intake f specific fatty acids and breast cancer risk amng pstmenpausal wmen in the VITAL chrt. Nutr Cancer. 2012;64(8): Larssn SC, Kumlin M, Ingelman-Sundberg M, Wlk A. Dietary lng-chain n-3 fatty acids fr the preventin f cancer: a review f ptential mechanisms. Am J Clin Nutr. 2004;79(6): Crsett PA, Cremna A, Mntrfan G, et al. Chemical-physical changes in cell membrane micrdmains f breast cancer cells after mega-3 PUFA incrpratin. Cell Bichem Biphys. 2012;64(1): Ca W, Ma Z, Rasenick MM, Yeh S, Yu J. N-3 ply-unsaturated fatty acids shift estrgen signaling t inhibit human breast cancer cell grwth. PLS One. 2012;7(12):e Rvit D, Girdan C, Vizza D, et al. Omega-3 PUFA ethanlamides DHEA and EPEA induce autphagy thrugh PPAR activatin in MCF-7 breast cancer cells. J Cell Physil. 2013;228(6): Murff HJ, Shu X-O, Li H, et al. Dietary plyunsaturated fatty acids and breast cancer risk in Chinese wmen: a prspective chrt study. Int J Cancer. 2011;128(6): Kim J, Lim S-Y, Shin A, et al. Fatty fish and fish mega-3 fatty acid intakes decrease the breast cancer risk: a case-cntrl study. BMC Cancer. 2009;9:

69 209. Chajès V, Trres-Mejía G, Biessy C, et al. W-3 and W-6 Plyunsaturated fatty acid intakes and the risk f breast cancer in Mexican wmen: impact f besity status. Cancer Epidemil Bimarkers Prev. 2012;21(2): De Bree E, Mamalakis G, Sanidas E, et al. Adipse tissue fatty acid cmpsitin in Greek patients with breast cancer versus thse with benign breast tumrs. Anticancer Res. 2013;33(4): Ga C-M, Ding J-H, Li S-P, Liu Y-T, Tang J-H, Tajima K. Intake f freshwater fish and assciated Fatty acids and risk f breast cancer. Asian Pac J Cancer Prev. 2014;15(18): Menendez JA, Lupu R, Clmer R. Exgenus supplementatin with mega-3 plyunsaturated fatty acid dcsahexaenic acid (DHA; 22:6n-3) synergistically enhances taxane cyttxicity and dwnregulates Her-2/neu (c-erbb-2) ncgene expressin in human breast cancer cells. Eur J Cancer Prev. 2005;14(3): Zheng J-S, Hu X-J, Zha Y-M, Yang J, Li D. Intake f fish and marine n-3 plyunsaturated fatty acids and risk f breast cancer: meta-analysis f data frm 21 independent prspective chrt studies. BMJ. 2013;346:f Rse DP, Cnnlly JM. Effects f fatty acids and eicsanid synthesis inhibitrs n the grwth f tw human prstate cancer cell lines. Prstate 1991;18(3): Faver A, Parpinel M, Franceschi S. Diet and risk f breast cancer: majr findings frm an Italian case-cntrl study. Bimed Pharmacther. 1998;52: Davis BC, Kris-Ethertn PM. Achieving ptimal essential fatty acid status in vegetarians: current knwledge and practical implicatins. Am J Clin Nutr. 2003;78(3 Suppl):640S-646S Gerster H. Can adults adequately cnvert alpha-linlenic acid (18:3n-3) t eicsapentaenic acid (20:5n-3) and dcsahexaenic acid (22:6n-3)? Int J Vitam Nutr Res. 1998;68(3): Alfan CM, Imayama I, Neuhuser ML, et al. Fatigue, inflammatin, and W-3 and W-6 fatty acid intake amng breast cancer survivrs. J Clin Oncl. 2012;30(12): Hutchins-Wiese HL, Pich K, Watkins BA, et al. High-dse eicsapentaenic acid and dcsahexaenic acid supplementatin reduces bne resrptin in pstmenpausal breast cancer survivrs n armatase inhibitrs: a pilt study. Nutr Cancer. 2014;66(1): Ghreishi Z, Esfahani A, Djazayeri A, et al. Omega-3 fatty acids are prtective against paclitaxelinduced peripheral neurpathy: a randmized duble-blind placeb cntrlled trial. BMC Cancer. 2012;12: Shim JY, An HJ, Lee YH, Kim SK, Lee KP, Lee KS. Overexpressin f cyclxygenase-2 is assciated with breast carcinma and its pr prgnstic factrs. Md Pathl. 2003;16(12): Snestedt E, Ericsn U, Gullberg B, Skg K, Olssn H, Wirfält E. D bth hetercyclic amines and mega-6 plyunsaturated fatty acids cntribute t the incidence f breast cancer in pstmenpausal wmen f the Malmö diet and cancer chrt? Int J Cancer Jul Thmsn CA, Guilian AR, Shaw JW, Rck CL, Ritenbaugh CK, Hakim IA, et al. Diet and bimarkers f xidative damage in wmen previusly treated fr breast cancer. Nutr Cancer 2005;51(2):

70 223. Chajes V, Bugnux P. Omega-6/mega-3 plyunsaturated fatty acid rati and cancer. Wrld Rev Nutr Diet 2003;92: Simpuls AP. The imprtance f the mega-6/mega-3 fatty acid rati in cardivascular disease and ther chrnic diseases. Exp Bil Med (Maywd). 2008;233(6): Kruk J, Marchlewicz M. Dietary fat and physical activity in relatin t breast cancer amng Plish wmen. Asian Pac J Cancer Prev. 2013;14(4): Taylr EF, Burley VJ, Greenwd DC, Cade JE. Meat cnsumptin and risk f breast cancer in the UK Wmen s Chrt Study. Br J Cancer. 2007;96(7): Di Pietr PF, Medeirs NI, Vieira FG, Faust MA, Belló-Klein A. Breast cancer in suthern Brazil: assciatin with past dietary intake. Nutr Hsp. 2007;22(5): Zheng W, Gustafsn DR, Sinha R, Cerhan JR, Mre D, Hng CP, et al. Well-dne meat intake and the risk f breast cancer. J Natl Cancer Inst. 1998;90(22): Fu Z, Deming SL, Fair AM, et al. Well-dne meat intake and meat-derived mutagen expsures in relatin t breast cancer risk: the Nashville Breast Health Study. Breast Cancer Res Treat. 2011;129(3): Pierce JP, Faerber S, Wright FA, Rck CL., Newman V, Flatt SW, et al. A randmized trial f the effect f a plant-based dietary pattern n additinal breast cancer events and survival: the Wmen s Healthy Eating and Living (WHEL) Study. Cntrlled Clin Trials 2002;23(6): Vikse R, Reistad R, Steffensen IL, Paulsen JE, Nyhlm SH, Alexander J, et al. [Hetercyclic amines in cked meat] [Article in Nrwegian] Tidsskrift fr den Nrske Laegefrening 1999;119(1): Feltn JS, Knize MG, Salmn CP, Malfatti MA, Kulp KS. Human expsure t hetercyclic amine fd mutagens/ carcingens: relevance t breast cancer. Envirn Ml Mutagen. 2002;39(2-3): Lauber SN, Gderham NJ. The cked meat-derived mammary carcingen 2-amin-1-methyl- 6-phenylimidaz[4,5-b]pyridine prmtes invasive behaviur f breast cancer cells. Txiclgy. 2011;279(1-3): Fergusn LR. Meat cnsumptin, cancer risk and ppulatin grups within New Zealand. Mutatin Res. 2002; : De Stefani E, Rnc A, Mendilaharsu M, Guidbn M, Dene-Pellegrini H. Meat intake, hetercyclic amines, and risk f breast cancer: a case-cntrl study in Uruguay. Cancer Epidemil Bimarkers Prev. 1997;6(8): Ta P, Li H, Wang Q, et al. [A case-cntrl study n assciatin f SULT1A1 plymrphism, smked meat intake with breast cancer risk]. Zhnghua Yu Fang Yi Xue Za Zhi. 2012;46(9): Delfin RJ, Sinha R, Smith C, West J, White E, Lin HJ, et al. Breast cancer, hetercyclic armatic amines frm meat and N-acetyltransferase 2 gentype. Carcingenesis 2000;21(4): Ambrsne CB, Freudenheim JL, Sinha R, Graham S, Marshall JR, Vena JE, et al. Breast cancer risk, meat cnsumptin and N-acetyltransferase (NAT2) genetic plymrphisms. Int J Cancer 1998;75(6): Sugimura T, Wakabayashi K, Nakagama H, Naga M. Hetercyclic amines: Mutagens/ carcingens prduced during cking f meat and fish. Cancer Sci. 2004;95(4):

71 240. Chudhary S, Sd S, Dnnell RL, Wang H-CR. Interventin f human breast cell carcingenesis chrnically induced by 2-amin-1-methyl-6-phenylimidaz[4,5-b]pyridine. Carcingenesis. 2012;33(4): Wilkinsn GR. The effects f diet, aging and disease-states n presystemic eliminatin and ral drug biavailability in humans. Adv Drug Delivery Rev. 1997;27(2-3): Deitz AC, Zheng W, Leff MA, et al. N-Acetyltransferase-2 genetic plymrphism, well-dne meat intake, and breast cancer risk amng pstmenpausal wmen. Cancer Epidemil Bimarkers Prev. 2000;9(9): Lee H, Wang Q, Yang F, et al. SULT1A1 Arg213His plymrphism, smked meat, and breast cancer risk: a case-cntrl study and meta-analysis. DNA Cell Bil. 2012;31(5): Chen WY, Willett WC, Rsner B, Clditz GA. Mderate alchl cnsumptin and breast cancer risk ASCO Annual Meeting, Abstract # Hrn-Rss PL, Canchla AJ, West DW, Stewart SL, Bernstein L, Deapen D, et al. Patterns f alchl cnsumptin and breast cancer risk in the Califrnia Teachers Study chrt. Cancer Epidemil Bimarkers Prev. 2004;13(3): Tjnneland A, Christensen J, Thmsen BL, Olsen A, Stripp C, Overvad K, et al. Lifetime alchl cnsumptin and pstmenpausal breast cancer rate in Denmark: a prspective chrt study. J Nutr. 2004;134(1): Hamajima N, Hirse K, Tajima K, Rhan T, Calle EE, Heath CW, et al. Alchl, tbacc and breast cancer--cllabrative reanalysis f individual data frm 53 epidemilgical studies, including 58,515 wmen with breast cancer and 95,067 wmen withut the disease. Br J Cancer 2002;87(11): Petri AL, Tjnneland A, Gambrg M, Jhansen D, Hidrup S, Srensen TI, et al. Alchl intake, type f beverage, and risk f breast cancer in pre- and pstmenpausal wmen. Alchl Clin Exp Res. 2004;28(7): Key TJ, Schatzkin A, Willett WC, Allen NE, Spencer EA, Travis RC. Diet, nutritin and the preventin f cancer. Public Health Nutr. 2004;7(1A): Berstad P, Ma H, Bernstein L, Ursin G. Alchl intake and breast cancer risk amng yung wmen. Breast Cancer Res Treat. 2008;108(1): Suzuki R, Orsini N, Mignne L, Saji S, Wlk A. Alchl intake and risk f breast cancer defined by estrgen and prgesterne receptr status--a meta-analysis f epidemilgical studies. Int J Cancer. 2008;122(8): Visvanathan K, Crum RM, Strickland PT, Yu X, Ruczinski I, Berndt SI, et al. Alchl dehydrgenase genetic plymrphisms, lw-t-mderate alchl cnsumptin, and risk f breast cancer. Alchl Clin Exp Res. 2007;31(3): Zhang SM, Lee IM, Mansn JE, Ck NR, Willett WC, Buring JE. Alchl cnsumptin and breast cancer risk in the Wmen s Health Study. Am J Epidemil. 2007;165(6): Wu AH, Vigen C, Razavi P, Tseng C-C, Stancyzk FZ. Alchl and breast cancer risk amng Asian-American wmen in Ls Angeles Cunty. Breast Cancer Res. 2012;14(6):R Chen WY, Rsner B, Hankinsn SE, Clditz GA, Willett WC. Mderate alchl cnsumptin during adult life, drinking patterns, and breast cancer risk. JAMA. 2011;306(17):

72 256. Smith-Warner SA, Spiegelman D, Yaun SS, van den Brandt PA, Flsm AR, Gldbhm RA, et al. Alchl and breast cancer in wmen: a pled analysis f chrt studies. JAMA. 1998;279(7): Lngnecker MP. Alchlic beverage cnsumptin in relatin t risk f breast cancer: metaanalysis and review. Cancer Causes Cntrl 1994;5(1): Ellisn RC, Zhang Y, McLennan CE, Rthman KJ. Explring the relatin f alchl cnsumptin t risk f breast cancer. Am J Epidemil. 2001;154(8): Bessaud F, Daurès JP. Patterns f Alchl (Especially Wine) Cnsumptin and Breast Cancer Risk: A Case-Cntrl Study amng a Ppulatin in Suthern France. Ann Epidemil Apr Liu Y, Clditz GA, Rsner B, et al. Alchl intake between menarche and first pregnancy: a prspective study f breast cancer risk. J Natl Cancer Inst. 2013;105(20): Enger SM, Rss RK, Paganini-Hill A, Lngnecker MP, Bernstein L. Alchl cnsumptin and breast cancer estrgen and prgesterne receptr status. Br J Cancer 1999;79(7-8): Suzuki R, Ye W, Rylander-Rudqvist T, Saji S, Clditz GA, Wlk A. Alchl and pstmenpausal breast cancer risk defined by estrgen and prgesterne receptr status: a prspective chrt study. J Natl Cancer Inst. 2005;97(21): Onland-Mret NC, Peeters PH, van der Schuw YT, Grbbee DE, van Gils CH. Alchl and endgenus sex sterid levels in pstmenpausal wmen: a crss-sectinal study. J Clin Endcrinl Metab. 2005;90(3): Hlmes MD. Des diet affect breast cancer risk? Breast Cancer Res. 2004;6(4): Drgan JF, Baer DJ, Albert PS, Judd JT, Brwn ED, Crle DK. Serum hrmnes and the alchlbreast cancer assciatin in pstmenpausal wmen. J Natl Cancer Inst. 2001;93(9): Maskarinec G, Mrimt Y, Takata Y, Murphy SP, Stanczyk FZ. Alchl and dietary fibre intakes affect circulating sex hrmnes amng premenpausal wmen. Public Health Nutr. 2006;9(7): Rinaldi S, Peeters PH, Bezemer ID, Dssus L, Biessy C, Sacerdte C, et al. Relatinship f alchl intake and sex sterid cncentratins in bld in pre- and pst-menpausal wmen: the Eurpean Prspective Investigatin int Cancer and Nutritin. Cancer Causes Cntrl. 2006;17(8): Sanchez-Alvarez R, Martinez-Outschrn UE, Lin Z, et al. Ethanl expsure induces the cancerassciated fibrblast phentype and lethal tumr metablism: implicatins fr breast cancer preventin. Cell Cycle. 2013;12(2): Sellers TA, Vierkant RA, Cerhan JR, Gapstur SM, Vachn CM, Olsn JE, et al. Interactin f dietary flate intake, alchl, and risk f hrmne receptr-defined breast cancer in a prspective study f pstmenpausal wmen. Cancer Epidemil Bimarkers Prev. 2002;11(10 Pt 1): Kritchevsky D. Calric restrictin and experimental mammary carcingenesis. Breast Cancer Res Treat. 1997;46(2-3): Meyer F, Bairati I, Fradet Y, Mre L. Dietary energy and nutrients in relatin t preclinical prstate cancer. Nutr Cancer 1997;29(2):

73 272. Snntag WE, Lynch CD, Cefalu WT, Ingram RL, Bennett, SA, Thrntn PL, et al. Pleitrpic effects f grwth hrmne and insulin-like grwth factr (IGF)-1 n bilgical aging: inferences frm mderate calric-restricted animals. The Jurnal f Gerntlgy. Series A, Bil Sci Med Sci. 1999;54(12):B521-B Yu H, Rhan T. Rle f the insulin-like grwth factr family in cancer develpment and prgressin. J Natl Cancer Inst. 2000;92(18): Feigelsn HS, Jnas CR, Teras LR, Thun MJ, Calle EE. Weight gain, bdy mass index, hrmne replacement therapy, and pstmenpausal breast cancer in a large prspective study. Cancer Epidemil Bimarkers Prev. 2004;13(2): Sweeney C, Blair CK, Andersn KE, Lazvich D, Flsm AR. Risk factrs fr breast cancer in elderly wmen. Am J Epidemil. 2004;160(9): Carpenter CL, Rss RK, Paganini-Hill A, Bernstein L. Effect f family histry, besity and exercise n breast cancer risk amng pstmenpausal wmen. Int J Cancer 2003;106(1): Key TJ, Verkasal PK, Banks E. Epidemilgy f breast cancer. Lancet Oncl. 2001;2: Mslly A, Gharbi O, Mahmudi K, Limem S, Hchlef M, et al. Assciatin between bdy mass index and risk f breast cancer in Tunisian wmen. Ann Saudi Med Jul-Aug;31(4): Phipps AI, Buist DS, Malne KE, Barlw WE, Prter PL, Kerlikwske K, O'Meara ES, Li CI. Breast density, bdy mass index, and risk f tumr marker-defined subtypes f breast cancer. Ann Epidemil May;22(5): Cheraghi Z, Prlajal J, Hashem T, Esmailnasab N, Dsti Irani A. Effect f bdy mass index n breast cancer during premenpausal and pstmenpausal perids: a meta-analysis. PLS One. 2012;7(12):e Kawai M, Minami Y, Nishin Y, Fukamachi K, Ohuchi N, Kakugawa Y. Bdy mass index and survival after breast cancer diagnsis in Japanese wmen. BMC Cancer Apr 17;12: Berstad P, Cates RJ, Bernstein L, Flger SG, Malne KE, Marchbanks PA, Weiss LK, Liff JM, McDnald JA, Strm BL, Simn MS, Deapen D, Press MF, Burkman RT, Spirtas R, Ursin G. A case-cntrl study f bdy mass index and breast cancer risk in white and African-American wmen. Cancer Epidemil Bimarkers Prev Jun;19(6): Biglia N, Pean E, Sgandurra P, Mggi G, Pecchi S, Maggirtt F, Sismndi P. Bdy mass index (BMI) and breast cancer: impact n tumr histpathlgic features, cancer subtypes and recurrence rate in pre and pstmenpausal wmen. Gynecl Endcrinl Mar;29(3): Cecchini RS, Cstantin JP, Cauley JA, Crnin WM, Wickerham DL, Land SR, Weissfeld JL, Wlmark N. Bdy mass index and the risk fr develping invasive breast cancer amng high-risk wmen in NSABP P-1 and STAR breast cancer preventin trials. Cancer Prev Res (Phila) Apr;5(4): Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D; Millin Wmen Study Cllabratin. Cancer incidence and mrtality in relatin t bdy mass index in the Millin Wmen Study: chrt study. BMJ. 2007;335(7630): Yumuk PF, Dane F, Yumuk VD, Yazici D, Ege B, Bekirglu N, et al. Impact f bdy mass index n cancer develpment. J BUON. 2008;13(1):

74 287. Iwasaki M, Otani T, Inue M, Sasazuki S, Tsugane S; fr the Japan Public Health Center-Based Prspective Study Grup. Bdy size and risk fr breast cancer in relatin t estrgen and prgesterne receptr status in Japan. Ann Epidemil. 2007;17(4): Eng SM, Gammn MD, Terry MB, Kushi LF, Teitelbaum SL, Brittn JA, et al. Bdy size changes in relatin t pstmenpausal breast cancer amng wmen n Lng Island, New Yrk. Am J Epidemil. 2005;162(3): Shi J, Zhang M, Li L, Hlman CD, Chen J, Teng Y, Liu Y. Bdy mass index and its change in adulthd and breast cancer risk in China. Asian Pac J Cancer Prev. 2010;11(5): Harvie M, Hper L, Hwell AH. Central besity and breast cancer risk: a systematic review. Obes Rev. 2003;4(3): Lahmann PH, Hffmann K, Allen N, van Gils CH, Khaw KT, Tehard B, Berrin F, et al. Bdy size and breast cancer risk: findings frm the Eurpean Prspective Investigatin int Cancer And Nutritin (EPIC). Int J Cancer 2004;111(5): Petekkaya I, Sahin U, Gezgen G, Slak M, Yuce D, Dizdar O, Arslan C, Ayyildiz V, Altundag K. Assciatin f breast cancer subtypes and bdy mass index. Tumri Mar- Apr;99(2): Ta MH, Marian C, Nie J, Ambrsne C, Krishnan SS, Edge SB, Trevisan M, Shields PG, Freudenheim JL. Bdy mass and DNA prmter methylatin in breast tumrs in the Western New Yrk Expsures and Breast Cancer Study. Am J Clin Nutr Sep;94(3): McTiernan A. Obesity and cancer: the risks, science, and ptential management strategies. Onclgy (Willistn Park). 2005;19(7): Dignam JJ, Wieand K, Jhnsn KA, Raich P, Andersn SJ, Smkin C. Effects f besity and race n prgnsis in lymph nde-negative, estrgen receptr-negative breast cancer. Breast Cancer Res Treat. 2005; Whiteman MK, Hillis SD, Curtis KM, McDnald JA, Wing PA, Marchbanks PA. Bdy mass and mrtality after breast cancer diagnsis. Cancer Epidemil Bimarkers Prev. 2005;14(8): Berclaz G, Li S, Price KN, Cates AS, Castigline-Gertsch M, Rudenstam CM, et al. Bdy mass index as a prgnstic feature in perable breast cancer: the Internatinal Breast Cancer Study Grup experience. Annal Oncl. 2004;15(6): Krenke CH, Chen, WY, Rsner B, Hlmes MD. Weight, weight gain, and survival after breast cancer diagnsis. J Clin Oncl. 2005;23(7): Ryu SY, Kim CB, Nam CM, Park JK, Kim KS, Park J, et al. Is bdy mass index the prgnstic factr in breast cancer?: a meta-analysis. J Krean Med Sci. 2001;16(5): Li S, Milne RL, Friedlander ML, McCredie MR, Giles GG, Hpper JL, et al. Obesity and utcmes in premenpausal and pstmenpausal breast cancer. Cancer Epidemil Bimarkers Prev. 2005;14(7): de Azambuja E, McCaskill-Stevens W, Francis P, Quinaux E, Crwn JP, et al. The effect f bdy mass index n verall and disease-free survival in nde-psitive breast cancer patients treated with dcetaxel and dxrubicin-cntaining adjuvant chemtherapy: the experience f the BIG trial. Breast Cancer Res Treat Jan;119(1):

75 302. Gnant M, Pfeiler G, Stöger H, Mlineritsch B, Fitzal F, Balic M, Kwasny W, Seifert M, Stierer M, Dubsky P, Greil R, Steger G, Samnigg H, Fesl C, Jakesz R. The predictive impact f bdy mass index n the efficacy f extended adjuvant endcrine treatment with anastrzle in pstmenpausal patients with breast cancer: an analysis f the randmised ABCSG-6a trial. Br J Cancer Aug 6;109(3): Kamineni A1, Andersn ML, White E, Taplin SH, Prter P, Ballard-Barbash R, Malne K, Buist DS. Bdy mass index, tumr characteristics, and prgnsis fllwing diagnsis f early-stage breast cancer in a mammgraphically screened ppulatin. Cancer Causes Cntrl Feb;24(2): Imkampe AK, Bates T. Impact f a raised bdy mass index n breast cancer survival in relatin t age and disease extent at diagnsis. Breast J Mar-Apr;16(2): Xing P, Li JG, Jin F, Zha TT, Liu Q, Dng HT, Wei XL. Prgnstic significance f bdy mass index in breast cancer patients with hrmne receptr-psitive tumurs after curative surgery. Clin Invest Med Dec 1;36(6):E Kwan ML, Chen WY, Krenke CH, Weltzien EK, Beasley JM, Nechuta SJ, Ple EM, Lu W, Hlmes MD, Quesenberry CP Jr, Pierce JP, Shu XO, Caan BJ. Pre-diagnsis bdy mass index and survival after breast cancer in the After Breast Cancer Pling Prject. Breast Cancer Res Treat Apr;132(2): Chen CH, L YF, Tsai HP, Shen SC, Cha TC, Chen MF, Chen SC. Lw bdy mass index is an independent risk factr f lcreginal recurrence in wmen with breast cancer underging breast cnserving therapy. Chang Gung Med J Sep-Oct;32(5): McTiernan A, Rajan KB, Twrger SS, Irwin M, Bernstein L, Baumgartner R, et al. Adipsity and Sex Hrmnes in Pstmenpausal Breast Cancer Survivrs. J Clin Oncl. 2003;21(10): Bagliett L, English DR, Hpper JL, Macinnis RJ, Mrris HA, Tilley WD, et al. Circulating sterid hrmne cncentratins in pstmenpausal wmen in relatin t bdy size and cmpsitin. Breast Cancer Res Treat May Hvidtfeldt UA, Gunter MJ, Lange T, et al. Quantifying mediating effects f endgenus estrgen and insulin in the relatin between besity, alchl cnsumptin, and breast cancer. Cancer Epidemil Bimarkers Prev. 2012;21(7): Pfeiler G, Königsberg R, Fesl C, Mlineritsch B, Steger H, Singer CF, Pöstlberger S, Steger GG, Seifert M, Dubsky P, Taucher S, Samnigg H, Bjelic-Radisic V, Greil R, Marth C, Gnant M. Impact f bdy mass index n the efficacy f endcrine therapy in premenpausal patients with breast cancer: an analysis f the prspective ABCSG-12 trial. J Clin Oncl Jul 1;29(19): Sendur MA, Aksy S, Zengin N, Altundag K. Efficacy f adjuvant armatase inhibitr in hrmne receptr-psitive pstmenpausal breast cancer patients accrding t the bdy mass index. Br J Cancer Nv 20;107(11): Ademuyiwa FO, Grman A, O'Cnnr T, Ambrsne C, Watrba N, Edge SB. Impact f bdy mass index n clinical utcmes in triple-negative breast cancer. Cancer Sep 15;117(18): Dawd S, Lei X, Littn JK, Buchhlz TA, Hrtbagyi GN, Gnzalez-Angul AM. Impact f bdy mass index n survival utcme amng wmen with early stage triple-negative breast cancer. Clin Breast Cancer Oct;12(5):

76 315. Gennari A, Nanni O, Puntni M, DeCensi A, Scarpi E, Cnte P, Antnucci G, Amadri D, Bruzzi P. Bdy mass index and prgnsis f metastatic breast cancer patients receiving first-line chemtherapy. Cancer Epidemil Bimarkers Prev Oct;22(10): Resta F, Triggiani V, Sabba C, Licchelli B, Ghiyasaldin S, Lis A, et al. The impact f bdy mass index and type 2 diabetes n breast cancer: current therapeutic measures f preventin. Curr Drug Targets Immune Endcr Metabl Disrd. 2004;4(4): Michels KB, Hlmberg L, Bergkvist L, Ljung H, Bruce A, Wlk A. Dietary antixidant vitamins, retinl, and breast cancer incidence in a chrt f Swedish wmen. Int J Cancer 2001;91(4): Ridner SH, Dietrich MS, Stewart BR, Armer JM. Bdy mass index and breast cancer treatmentrelated lymphedema. Supprt Care Cancer Jun;19(6): Hlmes MD, Chen WY, Feskanich D, Krenke CH, Clditz GA. Physical activity and survival after breast cancer diagnsis. JAMA 2005;293(20): McTiernan A, Kperberg C, White E, Wilcx S, Cates R, Adams-Campbell LL, et al. Recreatinal physical activity and the risk f breast cancer in pstmenpausal wmen: the Wmen s Health Initiative Chrt Study. JAMA 2003;290: Patel AV, Callel EE, Bernstein L, Wu AH, Thun MJ. Recreatinal physical activity and risk f pstmenpausal breast cancer in a large chrt f US wmen. Cancer Causes Cntrl 2003;14(6): Chen SS, Matthews CE, Bradshaw PT, Lipwrth L, Buchwski MS, Signrell LB, Blt WJ. Sedentary behavir, physical activity, and likelihd f breast cancer amng Black and White wmen: a reprt frm the Suthern Cmmunity Chrt Study. Cancer Prev Res (Phila) Jun;6(6): Friedenreich CM. The rle f physical activity in breast cancer etilgy. Semin Oncl Jun;37(3): Gnçalves AK, Dantas Flrenci GL, Maisnnette de Atayde Silva MJ, Cbucci RN, Girald PC, Cte NM. Effects f physical activity n breast cancer preventin: a systematic review. J Phys Act Health Feb;11(2): Hildebrand JS, Gapstur SM, Campbell PT, Gaudet MM, Patel AV. Recreatinal physical activity and leisure-time sitting in relatin t pstmenpausal breast cancer risk. Cancer Epidemil Bimarkers Prev Oct;22(10): Kawai M, Kakugawa Y, Nishin Y, Hamanaka Y, Ohuchi N, Minami Y. Anthrpmetric factrs, physical activity, and breast cancer risk in relatin t hrmne receptr and menpausal status in Japanese wmen: a case-cntrl study. Cancer Causes Cntrl May;24(5): Lynch BM, Neilsn HK, Friedenreich CM. Physical activity and breast cancer preventin. Recent Results Cancer Res. 2011;186: Prnk A, Ji BT, Shu XO, Chw WH, Xue S, Yang G, Li HL, Rthman N, Ga YT, Zheng W, Matthews CE. Physical activity and breast cancer risk in Chinese wmen. Br J Cancer Oct 25;105(9): Rinaldi S, Rmieu I, Wahrendrf J, Ribli E, Kaaks R. Physical activity and risk f breast cancer verall and by hrmne receptr status: the Eurpean prspective investigatin int cancer and nutritin. Int J Cancer Apr 1;132(7):

77 330. Sheppard VB, Makambi K, Taylr T, Wallingtn SF, Sween J, Adams-Campbell L. Physical activity reduces breast cancer risk in African American wmen. Ethn Dis Autumn;21(4): Suzuki R, Iwasaki M, Yamamt S, Inue M, Sasazuki S, Sawada N, Yamaji T, Shimazu T, Tsugane S; Japan Public Health Center-based Prspective Study Grup. Leisure-time physical activity and breast cancer risk defined by estrgen and prgesterne receptr status--the Japan Public Health Center-based Prspective Study. Prev Med Mar-Apr;52(3-4): Kruk J. Lifetime physical activity and the risk f breast cancer: a case-cntrl study. Cancer Detect Prev. 2007;31(1): Adams SA, Matthews CE, Hebert JR, Mre CG, Cunningham JE, Shu XO, et al. Assciatin f physical activity with hrmne receptr status: the Shanghai Breast Cancer Study. Cancer Epidemil Bimarkers Prev. 2006;15(6): Lahmann PH, Friedenreich C, Schuit AJ, Salvini S, Allen NE, Key TJ, et al. Physical activity and breast cancer risk: the Eurpean Prspective Investigatin int Cancer and Nutritin. Cancer Epidemil Bimarkers Prev. 2007;16(1): Dieli-Cnwright CM, Sullivan-Halley J, Patel A, Press M, Malne K, et al. Des hrmne therapy cunter the beneficial effects f physical activity n breast cancer risk in pstmenpausal wmen? Cancer Causes Cntrl Mar;22(3): Ta MH, Hainaut P, Marian C, Nie J, Ambrsne C, Edge SB, Trevisan M, Drn J, Shields PG, Freudenheim JL. Assciatin f prediagnstic physical activity with survival fllwing breast cancer diagnsis: influence f TP53 mutatin status. Cancer Causes Cntrl Dec;24(12): Cleveland RJ, Eng SM, Stevens J, Bradshaw PT, Teitelbaum SL, Neugut AI, Gammn MD. Influence f prediagnstic recreatinal physical activity n survival frm breast cancer. Eur J Cancer Prev Jan;21(1): Mnninkhf EM, Elias SG, Vlems FA, van der Tweel I, Schuit AJ, Vskuil DW, et al.; TFPAC. Physical activity and breast cancer: a systematic review. Epidemilgy. 2007;18(1): Kbayashi LC, Janssen I, Richardsn H, Lai AS, Spinelli JJ, Arnsn KJ. Mderate-t-vigrus intensity physical activity acrss the life curse and risk f pre- and pst-menpausal breast cancer. Breast Cancer Res Treat Jun;139(3): Hlick CN, Newcmb PA, Trentham-Dietz A, Titus-Ernstff L, Bersch AJ, Stampfer MJ, et al. Physical activity and survival after diagnsis f invasive breast cancer. Cancer Epidemil Bimarkers Prev. 2008;17(2): Zhng S, Jiang T, Ma T, Zhang X, Tang J, Chen W, Lv M, Zha J. Assciatin between physical activity and mrtality in breast cancer: a meta-analysis f chrt studies. Eur J Epidemil Jun;29(6): Bertram LA, Stefanick ML, Saquib N, Natarajan L, Pattersn RE, Bardwell W, Flatt SW, Newman VA, Rck CL, Thmsn CA, Pierce JP. Physical activity, additinal breast cancer events, and mrtality amng early-stage breast cancer survivrs: findings frm the WHEL Study. Cancer Causes Cntrl Mar;22(3): Williams PT. Significantly greater reductin in breast cancer mrtality frm pst-diagnsis running than walking. Int J Cancer Sep 1;135(5):

78 344. Irwin ML, McTiernan A, Mansn JE, Thmsn CA, Sternfeld B, Stefanick ML, Wactawski-Wende J, Craft L, Lane D, Martin LW, Chlebwski R. Physical activity and survival in pstmenpausal wmen with breast cancer: results frm the wmen's health initiative. Cancer Prev Res (Phila) Apr;4(4): Abrahamsn PE, Gammn MD, Lund MJ, Brittn JA, Marshall SW, Flagg EW, et al. Recreatinal physical activity and survival amng yung wmen with breast cancer. Cancer. 2006;107(8): Valenti M, Przi G, Aielli F, Verna L, Cannita K, Mann R, Masedu F, Marchetti P, Ficrella C. Physical exercise and quality f life in breast cancer survivrs. Int J Med Sci. 2008;5(1): Milne HM, Grdn S, Guilfyle A, Wallman KE, Curneya KS. Assciatin between physical activity and quality f life amng Western Australian breast cancer survivrs. Psychnclgy. 2007;16(12): Stagl JM, Antni MH, Lechner SC, Carver CS, Lewis JE. Pstsurgical physical activity and fatigue-related daily interference in wmen with nn-metastatic breast cancer. Psychl Health. 2014;29(2): Fntein DB, de Glas NA, Duijm M, Bastiaannet E, Prtielje JE, Van de Velde CJ, Liefers GJ. Age and the effect f physical activity n breast cancer survival: A systematic review. Cancer Treat Rev Dec;39(8): Campbell KL, Westerlind KC, Harber VJ, Bell GJ, Mackey JR, Curneya KS. Effects f aerbic exercise training n estrgen metablism in premenpausal wmen: a randmized cntrlled trial. Cancer Epidemil Bimarkers Prev. 2007;16(4): Ligibel JA, Campbell N, Partridge A, Chen WY, Salinardi T, Chen H, et al. Impact f a mixed strength and endurance exercise interventin n insulin levels in breast cancer survivrs. J Clin Oncl. 2008;26(6): Lynch BM, Friedenreich CM, Winkler EA, Healy GN, Vallance JK, Eakin EG, Owen N. Assciatins f bjectively assessed physical activity and sedentary time with bimarkers f breast cancer risk in pstmenpausal wmen: findings frm NHANES ( ). Breast Cancer Res Treat Nv;130(1): Irwin ML, Aiell EJ, McTiernan A, Bernstein L, Gilliland FD, Baumgartner RN, et al. Physical activity, bdy mass index, and mammgraphic density in pstmenpausal breast cancer survivrs. J Clin Oncl. 2007;25(9): Trres-Mejía G, Angeles-Llerenas A, Ortega-Olvera C, Lazcan-Pnce E, Ziv E, et al. Mderateintensity physical activity amelirates the breast cancer risk in diabetic wmen. Diabetes Care Dec;35(12): Pan SY, Zhu J, Gibbns L, Mrrisn H, Wen SW. Antixidants and breast cancer risk- a ppulatin-based case-cntrl study in Canada. BMC Cancer. 2011;11: Chidambaram N, Baradarajan A. Influence f selenium n glutathine and sme assciated enzymes in rats with mammary tumr induced by 7,12-dimethylbenz(a)anthracene. Ml Cell Bichem. 1996;156(2): Vadgama JV, Wu Y, Shen D, Hsia S, Blck J. Effect f selenium in cmbinatin with Adriamycin r Taxl n several different cancer cells. Anticancer Res. 2000;20(3A):

79 358. Lee SO, Nadiminty N, Wu XX, Lu W, Dng Y, Ip C, et al. Selenium disrupts estrgen signaling by altering estrgen receptr expressin and ligand binding in human breast cancer cells. Cancer Res. 2005;65(8): Liu JZ, Gilbert K, Parker HM, Haschek, WM, Milner JA. Inhibitin f 7,12-dimethylbenz(a) anthracene-induced mammary tumrs and DNA adducts by dietary selenite. Cancer Res. 1991;51(17): El-Bayumy K, Sinha R. Mechanisms f mammary cancer chempreventin by rganselenium cmpunds. Mutat Res. 2004;551(1-2): Li S, Zhu Y, Dng Y, Ip C. Dxrubicin and selenium cperatively induce fas signaling in the absence f Fas/Fas ligand interactin. Anticancer Res. 2007;27(5A): Harris HR, Bergkvist L, Wlk A. Selenium intake and breast cancer mrtality in a chrt f Swedish wmen. Breast Cancer Res Treat. 2012;134(3): Suzana S, Cham BG, Ahmad Rhi G, et al. Relatinship between selenium and breast cancer: a case-cntrl study in the Klang Valley. Singapre Med J. 2009;50(3): de Miranda JX, Andrade F de O, Cnti A de, Dagli MLZ, Mren FS, Ong TP. Effects f selenium cmpunds n prliferatin and epigenetic marks f breast cancer cells. J Trace Elem Med Bil Strain JJ, Bkje E, van t Veer P, Culter J, Stewart C, Lgan H, et al. Thyrid hrmnes and selenium status in breast cancer. Nutr Cancer 1997;27(1): Cann SA, van Netten JP, van Netten C. Hypthesis: idine, selenium and the develpment f breast cancer. Cancer Causes Cntrl 2000;11(2): Bunus G, Mlsn JH. The antixidant system. Anticancer Res. 2003;23(2B): Chen Y-C, Prabhu KS, Das A, Mastr AM. Dietary selenium supplementatin mdifies breast tumr grwth and metastasis. Int J Cancer. 2013;133(9): Chudhuri T, Pal S, Das T, Sa G. Curcumin selectively induces apptsis in deregulated cyclin D1-expressed cells at G2 phase f cell cycle in a p53-dependent manner. J Bil Chem. 2005;280(20): Mehta K, Pantazis P, McQueen T, Aggarwal BB. Antiprliferative effect f curcumin (diferulylmethane) against human breast tumr cell lines. Anticancer Drugs 1997;8(5): Aggarwal BB, Shishdia S, Takada Y, Banerjee S, Newman RA, Bues-Rams CE, et al. Curcumin suppresses the paclitaxel-induced nuclear factr-kappab pathway in breast cancer cells and inhibits lung metastasis f human breast cancer in nude mice. Clin Cancer Res. 2005;11(20): Sha ZM, Shen ZZ, Liu CH, Sartippur MR, G VL, Heber D, et al. Curcumin exerts multiple suppressive effects n human breast carcinma cells. Int J Cancer 2002;98(2): Jiang M, Huang O, Zhang X, et al. Curcumin induces cell death and restres tamxifen sensitivity in the antiestrgen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9. Mlecules. 2013;18(1): Liu D, Chen Z. The effect f curcumin n breast cancer cells. J Breast Cancer. 2013;16(2):

80 375. Masuelli L, Benvenut M, Fantini M, et al. Curcumin induces apptsis in breast cancer cell lines and delays the grwth f mammary tumrs in neu transgenic mice. J Bil Regul Hmest Agents. 27(1): Kang N, Wang M-M, Wang Y-H, et al. Tetrahydrcurcumin induces G2/M cell cycle arrest and apptsis invlving p38 MAPK activatin in human breast cancer cells. Fd Chem Txicl. 2014;67: Smasundaram S, Edmund NA, Mre DT, Small GW, Shi YY, et al. Dietary curcumin inhibits chemtherapy-induced apptsis in mdels f human breast cancer. Cancer Res Jul 1;62(13): Huang MT, Lu YR, Xie JG, Ma W, Lu YP., Yen P, et al. Effect f dietary curcumin and dibenzylmethane n frmatin f 7,12-dimethylbenz[a]anthracene-induced mammary tumrs and lymphmas/leukemias in Sencar mice. Carcingenesis 1998;19(9): Wallace JM. Nutritinal and btanical mdulatin f the inflammatry cascade--eicsanids, cyclxygenases, and lipxygenases--as an adjunct in cancer therapy. Integr Cancer Ther. 2002;1(1): Ramsewak RS, DeWitt DL, Nair MG. Cyttxicity, antixidant and anti-inflammatry activities f curcumins I-III frm Curcuma lnga. Phytmedicine 2000;7(4): Levi F, Pasche C, Lucchini F, La Vecchia C. Dietary intake f selected micrnutrients and breastcancer risk. Int J Cancer 2001;91(2): Hng SW, Jin DH, Hahm ES, Yim SH, Lim JS, Kim KI, et al. Ascrbate (vitamin C) induces cell death thrugh the apptsis-inducing factr in human breast cancer cells. Oncl Rep. 2007;18(4): Harris HR, Orsini N, Wlk A. Vitamin C and survival amng wmen with breast cancer: a metaanalysis. Eur J Cancer. 2014;50(7): Zhang SM. Rle f vitamins in the risk, preventin, and treatment f breast cancer. Curr Opin Obstet Gynecl. 2004;16(1): Bhlke K, Spiegelman D, Trichpulu A, Katsuvanni K, Trichpuls D. Vitamins A, C and E and the risk f breast cancer: results frm a case-cntrl study in Greece. Br J Cancer 1999;79(1): Nissen SB, Tjnneland A, Stripp C, Olsen A, Christensen J, Overvad K, et al. Intake f vitamins A, C, and E frm diet and supplements and breast cancer in pstmenpausal wmen. Cancer Causes Cntrl 2003;14(8): Verheven DT, Assen N, Gldbhm RA, Drant E, van t Veer P, Sturmans F, et al. Vitamins C and E, retinl, beta-cartene and dietary fibre in relatin t breast cancer risk: a prspective chrt study. Br J Cancer. 1997;75(1): Kushi LH, Fee RM, Sellers TA, Zheng W, Flsm AR. Intake f vitamins A, C, and E and pstmenpausal breast cancer. The Iwa Wmen s Health Study. Am J Epidemil. 1996;144(2): Negri E, La Vecchia C, Franceschi S, D Avanz B, Talamni R, Parpinel M, et al. Intake f selected micrnutrients and the risk f breast cancer. Int J Cancer. 1996;65(2): Singh P, Kapil U, Shukla NK, De S, Dwivedi SN. Assciatin between breast cancer and vitamin C, vitamin E and selenium levels: results f a case-cntrl study in India. Asian Pac J Cancer Prev. 2005;6(2):

81 392. Fleischauer AT, Simnsen N, Arab L. Antixidant supplements and risk f breast cancer recurrence and breast cancer- related mrtality amng pstmenpausal wmen. Nutr Cancer 2003;46(1): Harris HR, Bergkvist L, Wlk A. Vitamin C intake and breast cancer mrtality in a chrt f Swedish wmen. Br J Cancer. 2013;109(1): Mikirva N, Casciari J, Rgers A, Taylr P. Effect f high-dse intravenus vitamin C n inflammatin in cancer patients. J Transl Med. 2012;10: Suhail N, Bilal N, Khan HY, et al. Effect f vitamins C and E n antixidant status f breastcancer patients underging chemtherapy. J Clin Pharm Ther. 2012;37(1): Nesaretnam K, Ambra R, Selvaduray KR, Radhakrishan A, Canali R, Virgili F. Tctrienl-rich fractin frm palm il and gene expressin in human breast cancer cells. Ann NY Acad Sci. 2004;1031: Drjgch T, Shrubsle MJ, Shu XO, et al. Vitamin supplement use and risk fr breast cancer: the Shanghai Breast Cancer Study. Breast Cancer Res Treat. 2008;111(2): Peralta EA, Brewer AT, Luis S, Dunningtn GL. Vitamin E Increases Bimarkers f Estrgen Stimulatin When Taken With Tamxifen. J Surg Res Apr Alkhalaf M, El-Mwafy A, Renn W, Rachid O, Ali A, Al-Attyiah R. Resveratrl-induced apptsis in human breast cancer cells is mediated primarily thrugh the caspase-3-dependent pathway. Arch Med Res. 2008;39(2): Garvin S, Ollinger K, Dabrsin C. Resveratrl induces apptsis and inhibits angigenesis in human breast cancer xengrafts in viv. Cancer Lett. 2006;231(1): Whitsett T, Carpenter M, Lamartiniere CA. Resveratrl, but nt EGCG, in the diet suppresses DMBA-induced mammary cancer in rats. J Carcing. 2006;5: Tang FY, Su YC, Chen NC, Hsieh HS, Chen KS. Resveratrl inhibits migratin and invasin f human breast-cancer cells. Ml Nutr Fd Res. 2008;52(6): Singh B, Shulsn R, Chatterjee A, et al. Resveratrl inhibits estrgen-induced breast carcingenesis thrugh inductin f NRF2-mediated prtective pathways. Carcingenesis Aug;35(8): Vyas S, Asmerm Y, De León DD. Resveratrl regulates insulin-like grwth factr-ii in breast cancer cells. Endcrinlgy. 2005;146(10): Vetvicka V, Vlny T, Saraswat-Ohri S, Vashishta A, Vancikva Z, Vetvickva J. Glucan and resveratrl cmplex--pssible synergistic effects n immune system. Bimed Pap Med Fac Univ Palacky Olmuc Czech Repub. 2007;151(1): Chen F-P, Chien M-H. Phytestrgens induce differential effects n bth nrmal and malignant human breast cells in vitr. Climacteric. 2014: Dabrsin C, Chen J, Wang L, Thmpsn LU. Flaxseed inhibits metastasis and decreases extracellular vascular endthelial grwth factr in human breast cancer xengrafts. Cancer Letters 2002;185(1): Hutchins AM, Martini MC, Olsn BA, Thmas W, Slavin JL. Flaxseed cnsumptin influences endgenus hrmne cncentratins in pstmenpausal wmen. Nutr Cancer 2001;39(1):

82 409. Chen J, Pwer KA, Mann J, Cheng A, Thmpsn LU. Flaxseed alne r in cmbinatin with tamxifen inhibits MCF-7 breast tumr grwth in variectmized athymic mice with high circulating levels f estrgen. Exp Bil Med (Maywd). 2007;232(8): Thmpsn LU, Chen JM, Li T, Strasser-Weippl K, Gss PE. Dietary flaxseed alters tumr bilgical markers in pstmenpausal breast cancer. Clin Cancer Res. 2005;11(10): Chen J, Stavr PM, Thmpsn LU. Dietary flaxseed inhibits human breast cancer grwth and metastasis and dwnregulates expressin f insulin-like grwth factr and epidermal grwth factr receptr. Nutr Cancer 2002;43(2): Haggans CJ, Hutchins AM, Olsn BA, Thmas W, Martini MC, Slavin JL. Effect f flaxseed cnsumptin n urinary estrgen metablites in pstmenpausal wmen. Nutr Cancer 1999;33(2): Haggans CJ, Travelli EJ, Thmas W, Martini MC, Slavin JL. The effect f flaxseed and wheat bran cnsumptin n urinary estrgen metablites in premenpausal wmen. Cancer Epidemil. Bimarkers Prev. 2000;9(7): Lehraiki A, Attumbré J, Bienaimé C, et al. Extractin f lignans frm flaxseed and evaluatin f their bilgical effects n breast cancer MCF-7 and MDA-MB-231 cell lines. J Med Fd. 2010;13(4): Nagel G, Mack U, vn Furnier D, Linseisen J. Dietary phytestrgen intake and mammgraphic density -- results f a pilt study. Eur J Med Res. 2005;10(9): Flwer G, Fritz H, Balneaves LG, et al. Flax and Breast Cancer: A Systematic Review. Integr Cancer Ther. 2013;13(3): McCarty MF. A lw-fat, whle-fd vegan diet, as well as ther strategies that dwn-regulate IGF-I activity, may slw the human aging prcess. Med. Hyptheses 2003;60(6): Lee J, Ch K. Flaxseed spruts induce apptsis and inhibit grwth in MCF-7 and MDA-MB-231 human breast cancer cells. In Vitr Cell Dev Bil Anim. 2012;48(4): Lwcck EC, Ctterchi M, Bucher BA. Cnsumptin f flaxseed, a rich surce f lignans, is assciated with reduced breast cancer risk. Cancer Causes Cntrl. 2013;24(4): Masn JK, Chen J, Thmpsn LU. Flaxseed il-trastuzumab interactin in breast cancer. Fd Chem Txicl. 48(8-9): Sartippur MR, Heber D, Henning S, Elashff D, Elashff R, Rubi R, et al. cdna micrarray analysis f endthelial cells in respnse t green tea reveals a suppressive phentype. Int J Oncl. 2004;25(1): Takabayashi F, Tahara S, Kanek T, Harada N. Effect f green tea catechins n xidative DNA damage f hamster pancreas and liver induced by N-Nitrsbis(2-xprpyl)amine and/r xidized sybean il. Bifactrs 2004;21(1-4): Glei M, Pl-Zbel BL. The main catechin f green tea, (-)-epigallcatechin-3-gallate (EGCG), reduces blemycin-induced DNA damage in human leuccytes. Txicl In Vitr Sep Mittal A, Pate MS, Wylie RC, Tllefsbl TO, Katiyar SK. EGCG dwn-regulates telmerase in human breast carcinma MCF-7 cells, leading t suppressin f cell viability and inductin f apptsis. Int J Oncl. 2004;24(3):

83 425. Crespy V, Williamsn G. A review f the health effects f green tea catechins in in viv animal mdels. J Nutr. 2004;134(12 Suppl):3431S-3440S Thangapazham RL, Passi N, Maheshwari RK. Green tea plyphenl and epigallcatechin gallate induce apptsis and inhibit invasin in human breast cancer cells. Cancer Bil Ther. 2007;6(12): Gu S, Yang S, Taylr C, Snenshein GE. Green tea plyphenl epigallcatechin-3 gallate (EGCG) affects gene expressin f breast cancer cells transfrmed by the carcingen 7,12-dimethylbenz[a]anthracene. J Nutr. 2005;135(12 Suppl):2978S-2986S Wu AH, Tseng CC, Van Den Berg D, Yu MC. Tea intake, COMT gentype, and breast cancer in Asian-American wmen. Cancer Res. 2003;63(21): Baliga MS, Meleth S, Katiyar SK. Grwth inhibitry and antimetastatic effect f green tea plyphenls n metastasis- specific muse mammary carcinma 4T1 cells in vitr and in viv systems. Clin Cancer Res. 2005;11(5): Sun CL, Yuan JM, Kh WP, Yu MC. Green tea, black tea and breast cancer risk: a meta-analysis f epidemilgical studies. Carcingenesis 2006;27(7): Seely D, Mills EJ, Wu P, Verma S, Guyatt GH. The effects f green tea cnsumptin n incidence f breast cancer and recurrence f breast cancer: a systematic review and meta-analysis. Integr Cancer Ther. 2005;4(2): Wu AH, Yu Mc, Tseng CC, Hankin J, Pike MC. Green tea and risk f breast cancer in Asian Americans. Int J Cancer 2003;106(4): Zhang M, Hlman CD, Huang JP, Xie X. Green tea and the preventin f breast cancer: a casecntrl study in Sutheast China. Carcingenesis. 2007;28(5): Shrubsle MJ, Lu W, Chen Z, et al. Drinking green tea mdestly reduces breast cancer risk. J Nutr. 2009;139(2): Inue M, Tajima K, Mizutani M, Iwata H, Iwase T, Miura S, et al. Regular cnsumptin f green tea and the risk f breast cancer recurrence: fllw-up study frm the Hspital-based Epidemilgic Research Prgram at Aichi Cancer Center (HERPACC), Japan. Cancer Lett. 2001;167(2): Fujiki H, Suganuma M, Okabe S, Sueka E, Suga K, Imai K, et al. Mechanistic findings f green tea as cancer preventive fr humans. Prc Sc Exp Bil Med. 1999;220(4): Nakachi K, Suemasu K, Suga K, Take T, Imai K, Higashi Y. Influence f drinking green tea n breast cancer malignancy amng Japanese patients. Jpn J Cancer Res. 1998;89(3): Suzuki Y, Tsubn Y, Nakaya N, Suzuki Y, Kizumi Y, Tsuji I. Green tea and the risk f breast cancer: pled analysis f tw prspective studies in Japan. Br J Cancer 2004;90(7): Zhu JR, Yu L, Mai Z, Blackburn GL. Cmbined inhibitin f estrgen-dependent human breast carcinma by sy and tea biactive cmpnents in mice. Int J Cancer 2004;108(1): Thyagarajan A, Zhu J, Sliva D. Cmbined effect f green tea and Ganderma lucidum n invasive behavir f breast cancer cells. Int J Oncl. 2007;30(4): Sartippur MR, Pietras R, Marquez-Garban DC, Chen HW, Heber D, Henning SM, et al. The cmbinatin f green tea and tamxifen is effective against breast cancer. Carcingenesis. 2006;27(12):

84 442. Zeng L, Hlly JMP, Perks CM. Effects f physilgical levels f the green tea extract epigallcatechin-3-gallate n breast cancer cells. Frnt Endcrinl (Lausanne). 2014;5: Jenkins DJ, Kendall CW, D Csta MA, Jacksn CJ, Vidgen E, Singer W, et al. Sy cnsumptin and phytestrgens: effect n serum prstate specific antigen when bld lipids and xidized lw-density lipprtein are reduced in hyperlipidemic men. J Url. 2003;169(2): McCarty MF. Vegan prteins may reduce risk f cancer, besity, and cardivascular disease by prmting increased glucagn activity. Med Hyptheses 1999;53(6): Arliss RM, Biermann CA. D sy isflavnes lwer chlesterl, inhibit athersclersis, and play a rle in cancer preventin? Hlistic Nurs Pract. 2002;16(5): Setchell KD, Lydeking-Olsen E. Dietary phytestrgens and their effect n bne: evidence frm in vitr and in viv, human bservatinal, and dietary interventin studies. Am J Clin Nutr. 2003;78(3 Suppl):593S-609S H SC, W J, Lam S, Chen Y, Sham A, Lau J, et al. Sy prtein cnsumptin and bne mass in early pstmenpausal Chinese wmen. Oste Intl. 2003;14(10): Wu AH, Ziegler, Hrn-Rss PL, Nmura AM, West DW, Klnel LN, et al. Tfu and risk f breast cancer in Asian- Americans. Cancer Epidemil Bimarkers Prev. 1996;5(11): Hirse K, Imaeda N, Tkudme Y, Gt C, Wakai K, Matsu K, et al. Sybean prducts and reductin f breast cancer risk: a case-cntrl study in Japan. Br J Cancer 2005;93(1): Zhu Y, Zhu L, Jia S, Xu L. Relatinship between sy fd intake and breast cancer in China. Asian Pac J Cancer Prev. 2011;12(11): Travis RC, Allen NE, Appleby PN, Spencer EA, Rddam AW, Key TJ. A prspective study f vegetarianism and isflavne intake in relatin t breast cancer risk in British wmen. Int J Cancer. 2008;122(3): Caan BJ, Natarajan L, Parker B, et al. Sy fd cnsumptin and breast cancer prgnsis. Cancer Epidemil Bimarkers Prev. 2011;20(5): Chen M, Ra Y, Zheng Y, et al. Assciatin between sy isflavne intake and breast cancer risk fr pre- and pst-menpausal wmen: a meta-analysis f epidemilgical studies. PLS One. 2014;9(2):e Iwasaki M, Inue M, Otani T, Sasazuki S, Kurahashi N, Miura T, et al.; Japan Public Health Center-based prspective study grup. Plasma isflavne level and subsequent risk f breast cancer amng Japanese wmen: a nested case-cntrlstudy frm the Japan Public Health Center-based prspective study grup. J Clin Oncl. 2008;26(10): Wu AH, Yu MC, Tseng CC, Pike MC. Epidemilgy f sy expsures and breast cancer risk. Br J Cancer. 2008;98(1): Chi F, Wu R, Zeng Y-C, Xing R, Liu Y, Xu Z-G. Pst-diagnsis sy fd intake and breast cancer survival: a meta-analysis f chrt studies. Asian Pac J Cancer Prev. 2013;14(4): Kang H-B, Zhang Y-F, Yang J-D, Lu K-L. Study n sy isflavne cnsumptin and risk f breast cancer and survival. Asian Pac J Cancer Prev. 2012;13(3): Nagata C, Mizue T, Tanaka K, et al. Sy intake and breast cancer risk: an evaluatin based n a systematic review f epidemilgic evidence amng the Japanese ppulatin. Jpn J Clin Oncl. 2014;44(3):

85 459. Nechuta SJ, Caan BJ, Chen WY, et al. Sy fd intake after diagnsis f breast cancer and survival: an in-depth analysis f cmbined evidence frm chrt studies f US and Chinese wmen. Am J Clin Nutr. 2012;96(1): Shu XO, Zheng Y, Cai H, et al. Sy fd intake and breast cancer survival. JAMA. 2009;302(22): Wada K, Nakamura K, Tamai Y, et al. Sy isflavne intake and breast cancer risk in Japan: frm the Takayama study. Int J Cancer. 2013;133(4): Warri A, Saarinen NM, Makela S, Hilakivi-Clarke L. The rle f early life genistein expsures in mdifying breast cancer risk. Br J Cancer. 2008;98(9): Allred CD, Twaddle NC, Allred KF, Geppinger TS, Derge DR, Helferich WG. Sy prcessing influences grwth f estrgen-dependent breast cancer tumrs. Carcingenesis 2004;25: Allred CD, Twaddle NC, Allred KF, Geppinger TS, Churchwell MI, Ju YH, et al. Sy prcessing affects metablism and dispsitin f dietary isflavnes in variectmized BALB/c mice. J Agric Fd Chem. 2005;53(22): Byapati SM, Shu XO, Ruan ZX, Dai Q, Cai Q, Ga YT, et al. Syfd intake and breast cancer survival: a fllwup f the Shanghai Breast Cancer Study. Breast Cancer Res Treat. 2005;92(1): Nishi K, Niwa Y, Tyshima H, Tamakshi K, Knd T, Yatsuya H, et al. Cnsumptin f sy fds and the risk f breast cancer: findings frm the Japan Cllabrative Chrt (JACC) Study. Cancer Causes Cntrl. 2007;18(8): Zhang Y-F, Kang H-B, Li B-L, Zhang R-M. Psitive effects f sy isflavne fd n survival f breast cancer patients in China. Asian Pac J Cancer Prev. 2012;13(2): Kumar NB, Cantr A, Allen K, Riccardi D, Cx CE. The specific rle f isflavnes n estrgen metablism in premenpausal wmen. Cancer 2002;94(4): Xu X, Duncan AM, Merz BE, Kurzer MS. Effects f sy isflavnes n estrgen and phytestrgen metablism in premenpausal wmen. Cancer Epidemil Bimarkers Prev. 1998;7(12): Sandersn M, Shu XO, Yu H, Dai Q, Malin AS, Ga YT, et al. Insulin-like grwth factr-i, sy prtein intake, and breast cancer risk. Nutr Cancer 2004;50(1): Takata Y, Maskarinec G, Rinaldi S, Kaaks R, Nagata C. Serum insulin-like grwth factr-i levels amng wmen in Hawaii and Japan with different levels f tfu intake. Nutr Cancer. 2006;56(2): Wu AH, Pike MC, Williams LD, Spicer D, Tseng CC, Churchwell MI, et al. Tamxifen, sy, and lifestyle factrs in Asian American wmen with breast cancer. J Clin Oncl. 2007;25(21): Mai Z, Blackburn GL, Zhu JR. Genistein sensitizes inhibitry effect f tamxifen n the grwth f estrgen receptr- psitive and HER2-verexpressing human breast cancer cells. Ml Carcing. 2007;46(7): Shike M, Dane AS, Russ L, et al. The effects f sy supplementatin n gene expressin in breast cancer: a randmized placeb-cntrlled study. J Natl Cancer Inst. 2014;106(9). 85

86 475. Ingraham BA, Bragdn B, Nhe A. Mlecular basis f the ptential f vitamin D t prevent cancer. Curr Med Res Opin. 2008;24(1): Yusef FM, Jacbs ET, Kang PT, et al. Vitamin D status and breast cancer in Saudi Arabian wmen: case-cntrl study. Am J Clin Nutr. 2013;98(1): Tseng M, Byrne C, Evers KA, Daly MB. Dietary intake and breast density in high-risk wmen: a crss-sectinal study. Breast Cancer Res. 2007;9(5):R Givannucci E. Vitamin D and Cancer Incidence in the Harvard Chrts. Ann Epidemil Feb Abbas S, Linseisen J, Slanger T, Krpp S, Mutschelknauss EJ, Flesch-Janys D, et al. Serum 25-hydrxyvitamin D and risk f pst-menpausal breast cancer--results f a large case-cntrl study. Carcingenesis. 2008;29(1): Bauer SR, Hankinsn SE, Bertne-Jhnsn ER, Ding EL. Plasma vitamin D levels, menpause, and risk f breast cancer: dse-respnse meta-analysis f prspective studies. Medicine (Baltimre). 2013;92(3): Chen P, Li M, Gu X, et al. Higher bld 25(OH)D level may reduce the breast cancer risk: evidence frm a Chinese ppulatin based case-cntrl study and meta-analysis f the bservatinal studies. PLS One. 2013;8(1):e Rllisn DE, Cle AL, Tung K-H, et al. Vitamin D intake, vitamin D receptr plymrphisms, and breast cancer risk amng wmen living in the suthwestern U.S. Breast Cancer Res Treat. 2012;132(2): Hatse S, Lambrechts D, Verstuyf A, et al. Vitamin D status at breast cancer diagnsis: crrelatin with tumr characteristics, disease utcme, and genetic determinants f vitamin D insufficiency. Carcingenesis. 2012;33(7): Kim Y, Je Y. Vitamin D intake, bld 25(OH)D levels, and breast cancer risk r mrtality: a metaanalysis. Br J Cancer. 2014;110(11): Mhr SB, Grham ED, Kim J, Hfflich H, Garland CF. Meta-analysis f vitamin D sufficiency fr imprving survival f patients with breast cancer. Anticancer Res. 2014;34(3): Vrieling A, Seibld P, Jhnsn TS, et al. Circulating 25-hydrxyvitamin D and pstmenpausal breast cancer survival: Influence f tumr characteristics and lifestyle factrs? Int J Cancer. 2014;134(12): Maalmi H, Ordóñez-Mena JM, Schöttker B, Brenner H. Serum 25-hydrxyvitamin D levels and survival in clrectal and breast cancer patients: systematic review and meta-analysis f prspective chrt studies. Eur J Cancer. 2014;50(8): Heaney RP. Vitamin D in Health and Disease. Clin J Am Sc Nephrl Jun Bischff-Ferrari HA, Givannucci E, Willett WC, Dietrich T, Dawsn-Hughes B. Estimatin f ptimal serum cncentratins f 25-hydrxyvitamin D fr multiple health utcmes. Am J Clin Nutr. 2006;84(1): Wu AH, Wang R, Kh WP, Stanczyk FC, Lee HP, Yu MC. Sleep duratin, melatnin and breast cancer amng Chinese wmen in Singapre. Carcingenesis. 2008;29(6):

87 501. Schernhammer ES, Hankinsn SE. Light at night: a nvel risk factr fr cancer in shift wrkers? Clin Occup Envirn Med. 2003;3: Schernhammer ES, Krenke CH, Laden F, Hankinsn SE. Night wrk and risk f breast cancer. Epidemilgy. 2006;17(1): Franzese E, Nigri G. [Night wrk as a pssible risk factr fr breast cancer in nurses. Crrelatin between the nset f tumrs and alteratins in bld melatnin levels] [Article in Italian] Prf Inferm. 2007;60(2): Leman ES, Sisken BF, Zimmer S, Andersn KW. Studies f the interactins between melatnin and 2 Hz, 0.3 mt PEMF n the prliferatin and invasin f human breast cancer cells. Bielectrmagnetics 2001;22: Jardim-Perassi BV, Arbab AS, Ferreira LC, et al. Effect f melatnin n tumr grwth and angigenesis in xengraft mdel f breast cancer. PLS One. 2014;9(1):e Schernhammer ES, Hankinsn SE. Urinary melatnin levels and breast cancer risk. J Natl Cancer Inst. 2005;97(14): Jnes MP, Melan MA, Witt-Enderby PA. Melatnin decreases cell prliferatin and transfrmatin in a melatnin receptr- dependent manner. Cancer Lett. 2000;151: Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Esquifin AI, Cardinali DP, et al. Melatnin, envirnmental light, and breast cancer. Breast Cancer Res Treat. 2008;108(3): Lissni P, Barni S, Mandala M, et al. Decreased txicity and increased efficacy f cancer chemtherapy using the pineal hrmne melatnin in metastatic slid tumr patients with pr clinical status. Eur J Cancer 1999;35: Sanchez-Barcel EJ, Cs S, Mediavilla D, Martinez-Campa C, Gnzalez A, Alns-Gnzalez C. Melatnin-estrgen interactins in breast cancer. J Pineal Res. 2005;38(4): Srinivasan V, Pandi-Perumal SR, Brzezinski A, Bhatnagar KP, Cardinali DP. Melatnin, immune functin and cancer. Recent Pat Endcr Metab Immune Drug Discv. 2011;5(2): Lissni P, Barni S, Meregalli S, Fssati V, Cazzaniga M, Espsti D, et al. Mdulatin f cancer endcrine therapy by melatnin: a phase II study f tamxifen plus melatnin in metastatic breast cancer patients prgressing under tamxifen alne. Br J Cancer 1995;71: Lissni P, Palrssi F, Tancini G, Ardizzia A, Barni S, Brivi F, et al. A phase II study f tamxifen plus melatnin in metastatic slid tumur patients. Br J Cancer 1996;74: Hill SM, Cllins A, Kiefer TL. The mdulatin f estrgen receptr-alpha activity by melatnin in MCF-7 human breast cancer cells. Eur J Cancer 2000;36(Suppl 4): Viswanathan AN, Schernhammer ES. Circulating melatnin and the risk f breast and endmetrial cancer in wmen. Cancer Lett. 2009;281(1): Knwer KC, T SQ, Takagi K, et al. Melatnin suppresses armatase expressin and activity in breast cancer assciated fibrblasts. Breast Cancer Res Treat. 2012;132(2): Cs S, Martinez-Campa C, Mediavilla MD, Sanchez-Barcel EJ. Melatnin mdulates armatase activity in MCF-7 human breast cancer cells. J Pineal Res. 2005;38(2): del Ri B, Garcia Pedrer JM, Martinez-Campa C, Zuazua P, Laz PS, Rams S. Melatnin, an endgenus-specific inhibitr f estrgen receptr alpha via calmdulin. J Bil Chem. 2004;279(37):

88 519. Czeczuga-Semeniuk E, Wlczynski S, Anchim T, Dziecil J, Dabrwska M, Pietruczuk M. Effect f melatnin and all-trans retinic acid n the prliferatin and inductin f the appttic pathway in the culture f human breast cancer cell line MCF-7. Pl J Pathl. 2002;53(2): Margheri M, Pacini N, Tani A, et al. Cmbined effects f melatnin and all-trans retinic acid and smatstatin n breast cancer cell prliferatin and death: mlecular basis fr the anticancer effect f these mlecules. Eur J Pharmacl. 2012;681(1-3): Bizzarri M, Cucina A, Valente MG, Tagliaferri F, Brrelli V, Stipa F, et al. Melatnin and vitamin D3 increase TGF-beta1 release and induce grwth inhibitin in breast cancer cell cultures. J Surg Res. 2003;110(2): Institute f Medicine. Dietary Reference Intakes fr Calcium, Phsphrus, Magnesium, Vitamin D, and Fluride. Standing Cmmittee n the Scientific Evaluatin f Dietary Reference Intakes, Fd and Nutritin Bard Natinal Academy Press Natinal Osteprsis Fundatin Heaney RP. Bne bilgy in health and disease. In Mdern Nutritin in Health and Disease, 9th ed. Shils ME et al., eds Williams & Wilkins Chang YC, Parker J, Dley WC. Ht flash therapies in breast cancer survivrs. Supprt Cancer Ther. 2006;4(1): Su HI, Sammel MD, Springer E, Freeman EW, DeMichele A, Ma JJ. Weight gain is assciated with increased risk f ht flashes in breast cancer survivrs n armatase inhibitrs. Breast Cancer Res Treat. 2010;124(1): Ziaei S, Kazemnejad A, Zareai M. The effect f vitamin E n ht flashes in menpausal wmen. Gynecl Obstet Invest. 2007;64(4): Bartn DL, Lprinzi CL, Quella SK, Slan JA, Veeder MH, Egner JR, et al. Prspective evaluatin f vitamin E fr ht flashes in breast cancer survivrs. J Clin Oncl. 1998;16(2): Tempfer CB, Bentz EK, Ledlter S, Tscherne G, Reuss F, Crss HS, et al. Phytestrgens in clinical practice: a review f the literature. Fertil Steril. 2007;87(6): Lethaby AE, Brwn J, Marjribanks J, Krnenberg F, Rberts H, Eden J. Phytestrgens fr vasmtr menpausal symptms. Cchrane Database Syst Rev Oct 17;(4):CD Carrll DG. Nnhrmnal therapies fr ht flashes in menpause. Am Fam Physician. 2006;73(3): Pckaj BA, Gallagher JG, Lprinzi CL, Stella PJ, Bartn DL, Slan JA, et al. Phase III dubleblind, randmized, placeb- cntrlled crssver trial f black chsh in the management f ht flashes: NCCTG Trial N01CC1. J Clin Oncl. 2006;24(18): Ruhlen RL, Haubner J, Tracy JK, Zhu W, Ehya H, Lambersn WR, et al. Black chsh des nt exert an estrgenic effect n the breast. Nutr Cancer. 2007;59(2): Walji R, Bn H, Guns E, Oneschuk D, Yunus J. Black chsh (Cimicifuga racemsa [L.] Nutt.): safety and efficacy fr cancer patients. Supprt Care Cancer Aug;15(8): Tremblay A, Sheeran L, Aranda SK. Psycheducatinal interventins t alleviate ht flashes: a systematic review. Menpause. 2008;15(1):

89 536. Frisk JW, Hammar ML, Ingvar M, Spetz Hlm A-CE. Hw lng d the effects f acupuncture n ht flashes persist in cancer patients? Supprt Care Cancer. 2014;22(5): Park H, Parker GL, Bardman CH, Mrris MM, Smith TJ. A pilt phase II trial f magnesium supplements t reduce menpausal ht flashes in breast cancer patients. Supprt Care Cancer. 2011;19(6):

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