Low concentrations of 17β-estradiol exacerbate tamoxifen resistance in breast cancer treatment through membrane estrogen receptor-mediated signaling pathways.

The present study aims to discover the influences of tamoxifen and 17β-estradiol (E2) on tamoxifen-resistant (TamR) patients in vitro. Herein, we established a stabilized TamR MCF-7 cell line at 1 μM via gradient concentrations of tamoxifen cultivation. The expression changes of four ER subtypes (ERα66, ERβ, ERα36 and GPR30) were found to bring about tamoxifen resistance. Moreover, the generation of tamoxifen resistance involved in apoptosis escape via a reactive oxygen species-regulated p53 signaling pathway. Interestingly, E2 at environmental concentrations (0.1-10 nM) could activate the expression of both ERα36 and GPR30, and then stimulate the phosphorylation of ERK1/2 and Akt, resulting in cell growth promotion. Cell migration and invasion promotion, apoptosis inhibition, and cell cycle G1-S progression are involved in such proliferative effects. Conversely, the application of specific antagonists of ERα36 and GPR30 could restore tamoxifen's sensitivity as well as partially offset E2-mediated proliferation. In short, overexpression of ERα36 and GPR30 not only ablate tamoxifen responsiveness but also could promote tumor progression of TamR breast cancer under estrogen conditions. These results provided novel insights into underlying mechanisms of tamoxifen resistance and the negative effects of steroid estrogens at environmental concentrations on TamR MCF-7 cells, thus generating new thoughts for future management of ER-positive breast cancer.