The role of epidermal growth factor receptor in hepatocyte growth factor signaling in mammary epithelial cells

Deregulated hepatocyte growth factor (HGF) and c-Met signaling leads to increased tumor cell invasion and growth that is observed in mammary carcinogenesis. Determining the specific role of HGF/c-Met signaling in breast cancer has been compounded by the fact that c-Met communicates with a number other receptor pathways that lead to various pathological outcomes. In the present study we show that the epidermal growth factor receptor (EGFR) plays a direct role in HGF/c-Met mediated biological activities. We used the clinically relevant EGFR inhibitors gefitinib and erlotinib to determine the role of EGFR in mediating HGF signaling. Inhibition of EGFR through these small molecule inhibitors significantly reduces the ability of HGF to induce proliferation, cell motility and invasion as well as cell scattering in various mammary epithelial cells. Furthermore, our data indicate that gefitinib and erlotinib negatively regulate the ability of HGF to activate its cognate receptor c-Met and that this action is EGFR-dependent. Our results provide a novel mechanism of action for EGFR as a mediator of HGF signaling thereby linking EGFR to the oncogenic potential of c-Met in mammary carcinomas cells.