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

Abstract

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 facilitates 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 overexpression 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.

Resistance to hormone therapy in breast cancer cells promotes autophagy and EGFR signaling pathway

“…Notably, selective targeting of MAPK signaling with ERK inhibitors can resensitize EGFR overexpressing MCF-7 to Fulv ( 44 ). Upregulated EGFR/MEK1/MAPK1/2 signaling also occurs in 4-hydroxytamoxifen-resistant MCF-7 breast cancer cells and blocks BimEL-dependent apoptosis ( 55 ). The use of tyrosine kinase inhibitors has been previously described in some cases as a possible option to overcome hormone resistance ( 52 , 56 – 59 ).…”

“…Previous studies have proposed autophagy as a mechanism for 4-hydroxytamoxifen resistance ( 69 – 71 ). The 4-hydroxytamoxifen-resistant MCF-7 breast cancer cells can survive EGFR targeting by activating pro-survival autophagy ( 55 ). The induction of autophagy is responsible for the development of resistance to Tam in breast cancer cells ( 72 , 73 ).…”

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer

“…In a recent study by our laboratory, we identified the upregulation of the EGFR/MEK1/MAPK1/2 signaling axis in an estrogen resistant breast cancer cell model established from MCF-7 cells. In this study, we determined that pro-survival autophagy was attenuating the cytotoxic effects of MEK1 and EGFR inhibitor (selumetinib) treatment ( 225 ). Thus, autophagy may be a potential molecular target to improve targeted therapies aimed at the EGFR/MEK/MAPK1/2 signaling node in breast and other cancers.…”