Identifying Breast Cancer Oncogenes
Annual summary rept. 1 Oct 2009-30 Sep 2010
DANA-FARBER CANCER INST BOSTON MA
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Breast cancer is attributed to genetic alterations, the majority of which are yet to be characterized. Oncogenic alterations that give rise to breast tumors need to be identified in order to drive development of more efficient targeted or personalized cancer therapeutics and consequently, improve clinical outcomes. We aim to identify novel drivers of breast oncogenesis. We hypothesize that a kinase gain-of function screen in human mammary epithelial cells HMEC will reveal novel breast cancer oncogenes and provide potential targets for drug development. Our study is based on a transformation model that requires simultaneous activation of two RAS effector pathways PI3KAKT and MAPK, to transform human mammary epithelial cells. A pBabe-Puro-Myr-Flag kinase open reading frame ORF library was screened in immortalized human mammary epithelial cells HMLE expressing myr-AKT1 HMLEA. Three kinases PTK6, PAK1 and CAMK4 promoted robust anchorage-independent growth in soft agar and are further being validated to understand their mechanism of action and relevance in human cancer. Here, we report that PTK6 behaves as a cooperating oncogene to enhance human mammary transformation. In collaboration with Joan Brugges laboratory, we further determined that PTK6 activates IGF1R as well as RAS effector signaling to enhance anchorage-independent survival of mammary epithelial cells.
- Medicine and Medical Research