H Forschungszentrum für Umwelt und Gesundheit GmbH in der Helmholtzgemeinschaft Wissenschaftlich-Technische Abteilung Wissenschaftliche Highlights der GSF 2007 Abfrage April 2007 Institut / Selbst. Abteilung / KKG / Nachwuchsgruppe: FE-Nr.: 70311 Kontaktperson für Rückfragen: Michaela Aubele aubele@gsf.de 4132 Titel des Highlights: PTK (protein tyrosine kinase)-6 and Her2 & 4, but not Her1 & 3 predict long term survival in breast carcinomas Keywords: Her receptor family, protein tyrosine kinase 6 (PTK6), breast cancer, prognosis Kernaussage des Highlights in einem Satz: The cytoplasmic tyrosine kinase PTK6 is of prognostic relevance in breast cancer and may represent a novel therapy target Darstellung des Highlights: The HER receptors (in particular Her2/neu) are of therapeutic and prognostic significance in breast cancer, and their function is modulated by cytoplasmic tyrosine kinases like PTK6 (brk). It has been shown that the monoclonal antibody trastuzumab directed against Her2/neureceptor is therapeutically active in Her2/neu overexpressing breast carcinomas. However, a consistent number of Her2/neu-positive tumors are not responsive to this antibody therapy, indicating that simple oncogene overexpression may not account for the full malignant phenotype. In this study we investigated the protein expression of the HER receptor family (HER1/EGF-R; HER2/neu; HER3; HER4) and the cytoplasmic tyrosine kinase PTK6 in archival tissue from 193 breast carcinomas, and tested the association between markers and patient prognosis. In multivariate survival analysis for a metastases-free survival of patients (longer than 240 months) the stepwise selected parameters were tumor size, PTK6 protein expression, and number of positive lymph nodes. We demonstrated that PTK6 is a prognostic marker of metastases-free survival in breast cancer, and is independent of the classical morphological and molecular markers of lymph node involvement, tumor size, and HER2 status. Therefore, we hypothesise that PTK6 1
could be a cytoplasmic molecule influencing the biological response of HER receptor signaling, and may be usefull as novel therapeutic target in breast carcinomas. Michaela Aubele, Gert Auer, Axel K. Walch, Alison Munro, Mike J. Atkinson, Herbert Braselmann, Tommy Fornander, John M. S. Bartlett. 2007. PTK (protein tyrosine kinase)-6 and HER2 & 4, but not HER1 & 3 predict long term survival in breast carcinomas. Br J Cancer 96, 801-807. Bezug zur GSF-Strategie: Translational Research, Novel Target for Breast Cancer Therapy GSF-interne Kooperationspartner, mit denen das Highlight ggf. erarbeitet wurde: H. Braselmann, GSF - IMS, FE 70431 2
PTK (protein tyrosine kinase)-6 and Her receptors in breast cancer About 30 % of breast carcinomas show overexpression of the Her2/neu cell mebran receptor Her2/neu antibody therapie (Trastuzumab) response: Trastuzumab Monotherapy: 15-35% Trastuzumab + Chemotherapy: up to 70% searching for novel / additional therapy targets?
PTK (protein tyrosine kinase)-6 cytoplasmic non-receptor tyrosine kinase (BRK); expression = epithelial-specific elevated expression was found in breast cancer cell lines and in 2/3 of primary breast tumors in vitro studies showed, that PTK6 overexpression: - increases Her3 phosphorylation and Akt activation - sensitizes cells to EGF and co-precipitates with Her3 Function of PTK6 is unknown PTK6 protein possesses: protein tyrosine kinase domain SH2 domain SH3 domain regions enable it to protein-protein interactions
Results we found PTK6 overrepresented on DNA, mrna and on protein level in breast carcinomas AIB1.PCR1 AIB1.2 ADA AIB1.1 BCAS1 ZNF217 PTK6 ZNF218 GNAS MMP9 TOP1 SNAI1 PPIAL2 NCOA3 PTPN1.2 PTPN1.1 Screening of Chrom. 20q genes Immunhistochemie gene copy number Born et al. J Pathol 2006
Results Multivariate survival analysis classification of patients into 3 different risk groups according to their parameters: tumorsize / PTK6 protein expression / lymph node status low risk 1,0 medium risk low 91% event-free 0,8 probability probability 0,6 overall medium 71% event-free high risk 0,4 p<0.0001 high 43% event-free 0,2 0 50distant recurrence-free 100 survival 150 (months) 200 250 distant recurrence-free survival (months) Brit J Cancer 2007
Summary PTK6 expression is correlated with expression of Her receptors its protein expression correlates with clinical outcome of patients may modify HER receptor signaling in tumor cells and, therefore, may represent a novel therapy target in breast cancer