Estrogen receptor-alpha 36 mediates the anti-apoptotic effect of estradiol in triple negative breast cancer cells via a membrane-associated mechanism.

ABSTRACT: 17?-Estradiol can promote the growth and development of several estrogen receptor (ER)-negative breast cancers. The effects are rapid and non-genomic, suggesting that a membrane-associated ER is involved. ER?36 has been shown to mediate rapid, non-genomic, membrane-associated effects of 17?-estradiol in several cancer cell lines, including triple negative HCC38 breast cancer cells. Moreover, the effect is anti-apoptotic. The aim of this study was to determine if ER?36 mediates this anti-apoptotic effect, and to elucidate the mechanism involved. Taxol was used to induce apoptosis in HCC38 cells, and the effect of 17?-estradiol pre-treatment was determined. Antibodies to ER?36, signal pathway inhibitors, ER?36 deletion mutants, and ER?36-silencing were used prior to these treatments to determine the role of ER?36 in these effects and to determine which signaling molecules were involved. We found that the anti-apoptotic effect of 17?-estradiol in HCC38 breast cancer cells is in fact mediated by membrane-associated ER?36. We also showed that this signaling occurs through a pathway that requires PLD, LPA, and PI3K; G?s and calcium signaling may also be involved. In addition, dynamic palmitoylation is required for the membrane-associated effect of 17?-estradiol. Exon 9 of ER?36, a unique exon to ER?36 not found in other identified splice variants of ER? with previously unknown function, is necessary for these effects. This study provides a working model for a mechanism by which estradiol promotes anti-apoptosis through membrane-associated ER?36, suggesting that ER?36 may be a potential membrane target for drug design against breast cancer, particularly triple negative breast cancer.

SUBMITTER: Chaudhri RA 

PROVIDER: S-EPMC4296672 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature