Epidermal growth factor receptor and hepatocyte growth factor receptor act as redundant but independent inputs to promote survival to mammary epithelial cells and breast cancer cells

Breast cancer is the most common cancer and the second leading cause of cancer mortality in women with approximately one in eight being affected in their lifetime. Breast cancer is a complex and heterogeneous disease, with at least, five currently described subtypes that show different clinical course and response to therapeutic agents. Targeted therapies that inhibit receptor tyrosine kinases (RTKs) and the downstream signaling pathways have shown promising anticancer activity, but their efficacy in many solid tumors, including breast cancer, has been modest possibly because coactivation of different RTKs affects the response of tumor cells to targeted therapies. In this work we have analyzed the dependence of mammary epithelial cells and mammary tumor derived cell lines to RTK inhibition and how the downstream signaling is modulated. We found that MCF-10A and NMuMG as well as ERBB2 tumor derived cell lines are addicted to Epidermal Growth Factor Receptor (EGFR) for proliferation and survival. EGFR inhibition completely suppressed the ERK1/2 and the AKT pathways in these cell lines. Hepatocyte Growth Factor receptor (MET), but not other RTKs like insulin-like growth factor receptor or fibroblast growth factor receptor, was the only RTK that rendered anti-EGFR inhibition ineffective in extinguishing downstream signaling by replacing activated EGFR in the PI3K and MAPK complexes and by restoring cell viability and proliferation.