Adapter proteins are integrally involved in the intracellular regulation of diverse signaling events including the control of cellular proliferation, differentiation, adhesion, and motility. One of the key regulators in EGF receptor and c-Src signaling is the adapter protein p130Cas. Treatment of cells with EGF or EGF-related ligands leads to the phosphorylation and activation of p130Cas, which is augmented by the expression of c-Src. Deregulation of these pathways due to aberrant activation of EGF receptor family members or c-Src may contribute to the development of breast cancer, as elevated protein levels of p130Cas/BCAR1 in primary breast tumors are associated with poor prognosis and poor overall survival. We hypothesize that p130Cas is instrumental in the development and progression of tumors of the mammary gland induced by aberrant expression of EGF receptor-family tyrosine kinases and c-Src. The objectives of this application are to understand the biological role of p130Cas in breast cancer in vivo and during development of the mammary gland. Here experiments are proposed to use mouse models and cells in culture to characterize the role of p130Cas and its activation in tumorigenesis of breast epithelial cells; a combined approach correlating in vivo studies on function with in vitro analysis of mechanisms of action will be employed. Specifically aims are we proposed to: 1) Determine the functional role of p130Cas activity in breast cancer cells in vitro. 2) Analyze human breast tissue for gene amplifications leading to increased p130Cas. 3) Identify new signaling intermediates that interact physically with the p130Cas substrate domain in a tyrosine-dependent manner. 4) Determine the role of p130Cas in mammary gland development and breast cancer in vivo. These studies will provide important information on the role and mechanism of p130Cas expression in the pathogenesis of breast cancer and mammary gland development. The detailed knowledge of p130Cas in transformation and the identification of downstream effectors may uncover important new therapeutic targets for novel treatment modalities.
