Mechanism of c-Src Synergy with the EGFR In Breast Cancer

摘要

We have shown that inhibition of c-Src in breast tumor cells efficiently blocks tumor formation supporting the hypothesis that it may be an effective therapeutic target. In an effort to isolate a single domain of c-Src to target, we have demonstrated that the SH2 domain and surprisingly the kinase- inactive carboxy terminus of c-Src have inhibitory effects on tumorigenicity and growth of breast tumor cells. Furthermore, we have discovered a mechanism of c- Src synergy with the EGFR and located specific points at which the pathway can be interdicted. Specifically, we have shown that kinase-inactive c-Src is able to inhibit tumorigenicity of the I0T1/2 mouse fibroblast model cells by not phosphorylating the receptor on Tyr 845 in the activation loop of the kinase. The phosphorylation of Tyr 845 is required for EGF, serum, and LPA-induced DNA synthesis through the EGFR. This phosphorylation site in cancer cells presents an appealing target for cancer therapy of tumors that overexpress the EGFR and c-Src, such as breast cancer.