Tumorigenesis is a multi-step process the results in uncontrolled proliferation, invasion, and ultimately metastasis of tumor cells. This process frequently involves overexpression of signaling molecules otherwise involved in normal cellular proliferation and differentiation. Overexpression of the human epidermal growth factor receptor family (HER1/EGFR, HER2/neu, HER3, HER4) occurs in approximately 67 percent of human breast cancers. Overexpression of the non-receptor tyrosine kinase, c-Src, is found in close to 100 percent of breast tumors, and thus frequently accompanies EGFR overexpression. Since c-Src has been shown to potentiate EGF dependent DNA-synthesis in normal cells, co-overexpression of c-Src and EGFR in breast tumors suggests that c-Src may potentiate the role of HER family members in tumorigenesis. Human breast tumor cell lines which overexpress the EGFR and c-Src are characteristic of later stage tumors and poor prognosis. Identification of the downstream signaling molecules that are activated by overexpression of these two tyrosine kinases would provide targets for therapeutic intervention. The signal transducers and activators of transcription (STATs) are proteins that transmit a signal from a cytokine or growth factor receptor at the membrane of the cell to the nucleus where gene transcription is regulated. STATs are normally involved in the cellular process of proliferation, differentiation and apoptosis. Our preliminary evidence demonstrates that STAT proteins are activated in cells which overexpress the EGFR and c-Src in a manner dependent on EGFR kinase activity and c-Src mediated phosphorylation of the EGFR. Our hypothesis is that STAT proteins are one means by which a synergistic signal activated by EGFR and c-Src overexpression is transmitted to increase cell proliferation, transformation, and tumorigenesis. The following Specific Aims address this hypothesis: 1) Investigate the molecular mechanism of STAT5 activation in two tumorigenesis model systems; 2) Determine the role of STAT5 in transmitting the signal which leads to tumor function. The ultimate goal is that these studies will lead to the identification of novel therapeutic methods and/or reagents for treating breast cancer.
