title: Estrogen receptor-alpha 36 mediates the anti-apoptotic effect of estradiol in triple negative breast cancer cells via a membrane-associated mechanism.
abstract: 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-apoptotic effect, and to elucidate the mechanism involved. Taxol was used to induce apoptosis in HCC38 cells, and the effect of 17β-estradiol pre-treatment was determined. Antibodies to ERα36, signal pathway inhibitors, ERα36 deletion mutants, and ERα36-silencing were used prior to these treatments to determine the role of ERα36 in these effects and to determine which signaling molecules were involved. We found that the anti-apoptotic effect of 17β-estradiol in HCC38 breast cancer cells is in fact mediated by membrane-associated ERα36. We also showed that this signaling occurs through a pathway that requires PLD, LPA, and PI3K; Gαs and calcium signaling may also be involved. In addition, dynamic palmitoylation is required for the membrane-associated effect of 17β-estradiol. Exon 9 of ERα36, a unique exon to ERα36 not found in other identified splice variants of ERα 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 ERα36, suggesting that ERα36 may be a potential membrane target for drug design against breast cancer, particularly triple negative breast cancer.
authors.affiliation: The School of Biology and the Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA; Atlanta Clinical and Translational Science Institute, Emory University, Atlanta, GA, USA.
authors.forename: Reyhaan A
authors.initials: RA
authors.lastname: Chaudhri
authors.affiliation: The School of Biology and the Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Agreen
authors.initials: A
authors.lastname: Hadadi
authors.affiliation: The School of Biology and the Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Kirill S
authors.initials: KS
authors.lastname: Lobachev
authors.affiliation: School of Engineering, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Schwartz
authors.affiliation: The School of Biology and the Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA; School of Engineering, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: bboyan@vcu.edu.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Boyan
keywords: Anti-apoptosis; Breast cancer; Estrogen; Estrogen receptor-alpha 36; Plasma membrane; Taxol
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