Murine Models of Breast Cancer: Assessment of the Role of c-Src in Mammary Tumorigenesis

摘要

Strong evidence exists that the c-Src non-receptor tyrosine kinase plays a role in the pathology of human breast tumors. The purpose of this study was to examine the role of c-Src and its substrate Sin in mammary tumorigenesis using an animal model for breast cancer. In our experiments we characterized a signaling cascade that is activated as a result of Sin binding to Src and Src- mediated Sin phosphorylation, and involves activation of the small GTP-binding protein Rap1. More recently we found that Sin, when phosphorylated by Src kinases, forms a signaling complex consisting of signaling intermediates including the Src related tyrosine kinase Fyn, phospholypase C-gamma (PLC- gamma), and the adapter protein Crk. We also found that Sin regulates cell signaling by controlling the activation of PLC-gamma, which is important for proliferation in many different cell types. Recently, we generated Sin knockout mice which will be used in future experiments to address whether Sin is imp9rtant for mammary tumor formation by crossing these mice to existing mouse models of mammary tumorigenesis. These experiments will provide insight into the mechanisms of Src kinase/Sin-mediated tumorigenesis and may lead to the identification of proteins that will be used as targets for drug development.