Dataset Information

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

ACCESS DATA

Publications

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

Chaudhri Reyhaan A RA Hadadi Agreen A Lobachev Kirill S KS Schwartz Zvi Z Boyan Barbara D BD

Biochimica et biophysica acta 20140807 11

17β-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. ERα36 has been shown to mediate rapid, non-genomic, membrane-associated effects of 17β-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 ERα36 mediates this anti-apoptoti ...[more]

PMID: 25108195

Similar Datasets

Project description:Brain metastases (BM) are a devastating consequence of breast cancer. BM occur more frequently in patients with estrogen receptor-negative (ER-) breast cancer subtypes; HER2 overexpressing (HER2+) tumors and triple-negative (TN) (ER-, progesterone receptor-negative (PR-) and normal HER2) tumors. Young age is an independent risk factor for the development of BM, thus we speculated that higher circulating estrogens in young, pre-menopausal women could exert paracrine effects through the highly estrogen-responsive brain microenvironment. Using a TN experimental metastases model, we demonstrate that ovariectomy decreased the frequency of magnetic resonance imaging-detectable lesions by 56% as compared with estrogen supplementation, and that the combination of ovariectomy and letrozole further reduced the frequency of large lesions to 14.4% of the estrogen control. Human BM expressed 4.2-48.4% ER+ stromal area, particularly ER+ astrocytes. In vitro, E2-treated astrocytes increased proliferation, migration and invasion of 231BR-EGFP cells in an ER-dependent manner. E2 upregulated epidermal growth factor receptor (EGFR) ligands Egf, Ereg and Tgfa mRNA and protein levels in astrocytes, and activated EGFR in brain metastatic cells. Co-culture of 231BR-EGFP cells with E2-treated astrocytes led to the upregulation of the metastatic mediator S100 Calcium-binding protein A4 (S100A4) (1.78-fold, P<0.05). Exogenous EGF increased S100A4 mRNA levels in 231BR-EGFP cells (1.40±0.02-fold, P<0.01 compared with vehicle control) and an EGFR/HER2 inhibitor blocked this effect, suggesting that S100A4 is a downstream effector of EGFR activation. Short hairpin RNA-mediated S100A4 silencing in 231BR-EGFP cells decreased their migration and invasion in response to E2-CM, abolished their increased proliferation in co-cultures with E2-treated astrocytes and decreased brain metastatic colonization. Thus, S100A4 is one effector of the paracrine action of E2 in brain metastatic cells. These studies provide a novel mechanism by which estrogens, acting through ER+ astrocytes in the brain microenvironment, can promote BM of TN breast cancers, and suggests existing endocrine agents may provide some clinical benefit towards reducing and managing BM.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets