Upregulation of the EGFR/MEK1/MAPK1/2 signaling axis as a mechanism of resistance to antiestrogen-induced BimEL dependent apoptosis in ER⁺ breast cancer cells

The epidermal growth factor receptor (EGFR) is commonly upregulated in multiple cancer types, including breast cancer. In the present study, evidence is provided in support of the premise that upregulation of the EGFR/MEK1/MAPK1/2 signaling axis during antiestrogen treatment facili- tates the escape of breast cancer cells from BimEL-dependent apoptosis, conferring resistance to therapy. This conclusion is based on the findings that ectopic BimEL cDNA overexpres- sion and confocal imaging studies confirm the pro-apoptotic role of BimEL in ERα expressing breast cancer cells and that upregulated EGFR/MEK1/MAPK1/2 signaling blocks BimEL pro-apoptotic action in an antiestrogen-resistant breast cancer cell model. In addition, the present study identified a pro-survival role for autophagy in antiestrogen resistance while EGFR inhibitor studies demonstrated that a significant percentage of antiestrogen-resistant breast cancer cells survive EGFR targeting by pro-survival autophagy. These pre-clinical studies establish the possibility that targeting both the MEK1/MAPK1/2 signaling axis and pro-survival autophagy may be required to eradicate breast cancer cell survival and prevent the development of antiestrogen resistance following hormone treatments. The present study uniquely identified EGFR upregulation as one of the mechanisms breast cancer cells utilize to evade the cytotoxic effects of antiestrogens mediated through BimEL-dependent apoptosis.