Reyhaan A Chaudhri1, Agreen Hadadi2, Kirill S Lobachev2, Zvi Schwartz3, Barbara D Boyan4. 1. 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. 2. The School of Biology and the Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA. 3. School of Engineering, Virginia Commonwealth University, Richmond, VA, USA. 4. 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.
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.
17β-pan class="Chemical">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 HCC38breast 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 HCC38breast 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: Melissa A Maczis; Michael Maceyka; Michael R Waters; Jason Newton; Manjulata Singh; Madisyn F Rigsby; Tia H Turner; Mohammad A Alzubi; J Chuck Harrell; Sheldon Milstien; Sarah Spiegel Journal: J Lipid Res Date: 2018-10-12 Impact factor: 5.922
Authors: Chi-Chih Kang; Toby M Ward; Jessica Bockhorn; Courtney Schiffman; Haiyan Huang; Mark D Pegram; Amy E Herr Journal: NPJ Precis Oncol Date: 2018-03-22