Functional Interactions Between c-Src and HER1 Potentiate Neoplastic Transformation: Implications for the Etiology of Human Breast Cancer

Previous work from our laboratory has shown that c-Src and the EGFR interact synergistically in a fibroblasts model system to potentiate mitogenesis and tumorigenesis, providing a model system for the study of human breast cancer. We have identified a c-Src-dependent phosphorylation of the EGFR, Tyr 845, which is required for EGF and serum induced mitogenesis. Here, I show that G-protein coupled and cytokine receptor coupled signaling pathways are able to induce phosphorylation of the EGFR on Tyr 845, and that c-Src kinase activity is required for this phosphorylation to occur. Moreover, expression of a Y845F form of the EGFR in fibroblasts decreases DNA synthesis in response to at least two GPCR agonists endothelin and LPA. Crosstalk also appears to exist between the EGFR signaling pathway and hat regulated by the steroid hormone estrogen, in that estrogen dependent DNA synthesis in MCF7 cells an be reduced to nonstimulated levels by the introduction of a Y845F mutant form of the EGFR. Taken together, these data suggest that phosphorylation of EGFR Tyr 845 is a central, critical event that is common to a variety of mitogenic signaling pathways.