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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA106468-03
Application #
7162540
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Spalholz, Barbara A
Project Start
2005-01-01
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
3
Fiscal Year
2007
Total Cost
$282,526
Indirect Cost
Name
Boston University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Kumbrink, Joerg; Soni, Shefali; Laumbacher, Barbara et al. (2015) Identification of Novel Crk-associated Substrate (p130Cas) Variants with Functionally Distinct Focal Adhesion Kinase Binding Activities. J Biol Chem 290:12247-55
Zhao, Yingshe; Kumbrink, Joerg; Lin, Bor-Tyh et al. (2013) Expression of a phosphorylated substrate domain of p130Cas promotes PyMT-induced c-Src-dependent murine breast cancer progression. Carcinogenesis 34:2880-90
Kumbrink, Joerg; Kirsch, Kathrin H (2013) p130Cas acts as survival factor during PMA-induced apoptosis in HL-60 promyelocytic leukemia cells. Int J Biochem Cell Biol 45:531-5
Kumbrink, Joerg; Kirsch, Kathrin H (2012) Regulation of p130(Cas)/BCAR1 expression in tamoxifen-sensitive and tamoxifen-resistant breast cancer cells by EGR1 and NAB2. Neoplasia 14:108-20
Min, Chengyin; Zhao, Yingshe; Romagnoli, Mathilde et al. (2010) Lysyl oxidase propeptide sensitizes pancreatic and breast cancer cells to doxorubicin-induced apoptosis. J Cell Biochem 111:1160-8
Kumbrink, Joerg; Kirsch, Kathrin H; Johnson, Judith P (2010) EGR1, EGR2, and EGR3 activate the expression of their coregulator NAB2 establishing a negative feedback loop in cells of neuroectodermal and epithelial origin. J Cell Biochem 111:207-17
Min, Chengyin; Yu, Ziyang; Kirsch, Kathrin H et al. (2009) A loss-of-function polymorphism in the propeptide domain of the LOX gene and breast cancer. Cancer Res 69:6685-93
Soni, Shefali; Lin, Bor-Tyh; August, Avery et al. (2009) Expression of a phosphorylated p130(Cas) substrate domain attenuates the phosphatidylinositol 3-kinase/Akt survival pathway in tamoxifen resistant breast cancer cells. J Cell Biochem 107:364-75
Zhao, Yingshe; Min, Chengyin; Vora, Siddharth R et al. (2009) The lysyl oxidase pro-peptide attenuates fibronectin-mediated activation of focal adhesion kinase and p130Cas in breast cancer cells. J Biol Chem 284:1385-93
Gaidos, Gabriel; Soni, Shefali; Oswald, Duane J et al. (2007) Structure and function analysis of the CMS/CIN85 protein family identifies actin-bundling properties and heterotypic-complex formation. J Cell Sci 120:2366-77