4.7 Article

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

期刊

ENVIRONMENTAL TOXICOLOGY
卷 37, 期 3, 页码 514-526

出版社

WILEY
DOI: 10.1002/tox.23417

关键词

17 beta-estradiol; breast cancer; estrogen receptors; in vitro; reactive oxygen species; tamoxifen resistance

资金

  1. National Natural Science Foundation of China [21567014]
  2. China Postdoctoral Science Foundation [2019M653846XB]

向作者/读者索取更多资源

The study demonstrated that environmental concentrations of E2 can promote cell growth, migration, invasion, apoptosis inhibition, and G1-S progression in tamoxifen-resistant patients. Overexpression of ERα36 and GPR30 can restore tamoxifen sensitivity and partially offset the proliferative effects mediated by E2.
Y The present study aims to discover the influences of tamoxifen and 17 beta-estradiol (E2) on tamoxifen-resistant (TamR) patients in vitro. Herein, we established a stabilized TamR MCF-7 cell line at 1 mu M via gradient concentrations of tamoxifen cultivation. The expression changes of four ER subtypes (ER alpha 66, ER beta, ER alpha 36 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 ER alpha 36 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 ER alpha 36 and GPR30 could restore tamoxifen's sensitivity as well as partially offset E2-mediated proliferation. In short, overexpression of ER alpha 36 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.

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