Continuous Exposure of Breast Cancer Cells to Tamoxifen Upregulates GPER-1 and Increases Cell Proliferation
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Date
Authors
ORTLOFF TRAUTMANN, ALEXANDER
Molina, Luis
Bustamante, Felipe A.
Ortloff, Alexander R.
Ramos, Iraidi
Ehrenfeld, Pamela
Figueroa, Carlos D.
Molina, Luis
Bustamante, Felipe A.
Ortloff, Alexander R.
Ramos, Iraidi
Ehrenfeld, Pamela
Figueroa, Carlos D.
Authors
Date
Datos de publicación:
10.3389/fendo.2020.563165
Keywords
Breast Cancer - Calcium Signaling - Cell Proliferation - G1 Agonist - Gper-1, Gpr30 - Kinin B1 Receptor - Tamoxifen Resistance - Dimethyl Sulfoxide - Leupeptin - Peroxidase - Tamoxifen - Buffer - Calcium Chelating Agent - Dimethyl Sulfoxide - G Protein Coupled Receptor 30 - Kinin - Kinin B1 Receptor - Leupeptin - Peroxidase - Tamoxifen - Unclassified Drug - Article - Breast Cancer - Breast Cancer Cell Line - Breast Tumor - Calcium Mobilization - Cancer Growth - Cancer Patient - Cell Proliferation - Cell Proliferation Assay - Controlled Study - Female - Gene - Gene Expression - Gene Overexpression - Gper 1 Gene - Human - Human Cell - Immunodetection - In Vitro Study - Mcf-7 Cell Line - Mobilization - Polyacrylamide Gel Electrophoresis - Upregulation - Western Blotting
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Abstract
GPER-1 is a novel membrane sited G protein-coupled estrogen receptor. Clinical studies have shown that patients suffering an estrogen receptor ? (ER?)/GPER-1 positive, breast cancer have a lower survival rate than those who have developed ER?-positive/GPER-1 negative tumors. Moreover, absence of GPER-1 improves the prognosis of patients treated with tamoxifen, the most used selective estrogen receptor modulator to treat ER?-positive breast cancer. MCF-7 breast cancer cells were continuously treated with 1,000 nM tamoxifen for 7 days to investigate its effect on GPER-1 protein expression, cell proliferation and intracellular [Ca2+]i mobilization, a key signaling pathway. Breast cancer cells continuously treated with tamoxifen, exhibited a robust [Ca2+]i mobilization after stimulation with 1,000 nM tamoxifen, a response that was blunted by preincubation of cells with G15, a commercial GPER-1 antagonist. Continuously treated cells also displayed a high [Ca2+]i mobilization in response to a commercial GPER-1 agonist (G1) and to estrogen, in a magnitude that doubled the response observed in untreated cells and was almost completely abolished by G15. Proliferation of cells continuously treated with tamoxifen and stimulated with 2,000 nM tamoxifen, was also higher than that observed in untreated cells in a degree that was approximately 90% attributable to GPER-1. Finally, prolonged tamoxifen treatment did not increase ER? expression, but did overexpress the kinin B1 receptor, another GPCR, which we have previously shown is highly expressed in breast tumors and increases proliferation of breast cancer cells. Although we cannot fully extrapolate the results obtained in vitro to the patients, our results shed some light on the occurrence of drug resistance in breast cancer patients who are ER?/GPER-1 positive, have been treated with tamoxifen and display low survival rate. Overexpression of kinin B1 receptor may explain the increased proliferative response observed in breast tumors under continuous treatment with tamoxifen. © 2020 Elsevier B.V., All rights reserved.
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Keywords
Breast Cancer , Calcium Signaling , Cell Proliferation , G1 Agonist , Gper-1, Gpr30 , Kinin B1 Receptor , Tamoxifen Resistance , Dimethyl Sulfoxide , Leupeptin , Peroxidase , Tamoxifen , Buffer , Calcium Chelating Agent , Dimethyl Sulfoxide , G Protein Coupled Receptor 30 , Kinin , Kinin B1 Receptor , Leupeptin , Peroxidase , Tamoxifen , Unclassified Drug , Article , Breast Cancer , Breast Cancer Cell Line , Breast Tumor , Calcium Mobilization , Cancer Growth , Cancer Patient , Cell Proliferation , Cell Proliferation Assay , Controlled Study , Female , Gene , Gene Expression , Gene Overexpression , Gper 1 Gene , Human , Human Cell , Immunodetection , In Vitro Study , Mcf-7 Cell Line , Mobilization , Polyacrylamide Gel Electrophoresis , Upregulation , Western Blotting
Citation
10.3389/fendo.2020.563165