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Dual Epigenetic Regulation of ERα36 Expression in Breast Cancer Cells

Breast cancer remains the major cause of cancer-induced morbidity and mortality in women. Among the different molecular subtypes, luminal tumors yet considered of good prognosis often develop acquired resistance to endocrine therapy. Recently, misregulation of ERα36 was reported to play a crucial ro...

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Autores principales: Thiebaut, Charlène, Chesnel, Amand, Merlin, Jean-Louis, Chesnel, Maelle, Leroux, Agnès, Harlé, Alexandre, Dumond, Hélène
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600239/
https://www.ncbi.nlm.nih.gov/pubmed/31146345
http://dx.doi.org/10.3390/ijms20112637
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author Thiebaut, Charlène
Chesnel, Amand
Merlin, Jean-Louis
Chesnel, Maelle
Leroux, Agnès
Harlé, Alexandre
Dumond, Hélène
author_facet Thiebaut, Charlène
Chesnel, Amand
Merlin, Jean-Louis
Chesnel, Maelle
Leroux, Agnès
Harlé, Alexandre
Dumond, Hélène
author_sort Thiebaut, Charlène
collection PubMed
description Breast cancer remains the major cause of cancer-induced morbidity and mortality in women. Among the different molecular subtypes, luminal tumors yet considered of good prognosis often develop acquired resistance to endocrine therapy. Recently, misregulation of ERα36 was reported to play a crucial role in this process. High expression of this ERα isoform was associated to preneoplastic phenotype in mammary epithelial cells, disease progression, and enhanced resistance to therapeutic agents in breast tumors. In this study, we identified two mechanisms that could together contribute to ERα36 expression regulation. We first focused on hsa-miR-136-5p, an ERα36 3’UTR-targeting microRNA, the expression of which inversely correlated to the ERα36 one in breast cancer cells. Transfection of hsa-miR136-5p mimic in MCF-7 cells resulted in downregulation of ERα36. Moreover, the demethylating agent decitabine was able to stimulate hsa-miR-136-5p endogenous expression, thus indirectly decreasing ERα36 expression and counteracting tamoxifen-dependent stimulation. The methylation status of ERα36 promoter also directly modulated its expression level, as demonstrated after decitabine treatment of breast cancer cell and confirmed in a set of tumor samples. Taken together, these results open the way to a direct and an indirect ERα36 epigenetic modulation by decitabine as a promising clinical strategy to counteract acquired resistance to treatment and prevent relapse.
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spelling pubmed-66002392019-07-16 Dual Epigenetic Regulation of ERα36 Expression in Breast Cancer Cells Thiebaut, Charlène Chesnel, Amand Merlin, Jean-Louis Chesnel, Maelle Leroux, Agnès Harlé, Alexandre Dumond, Hélène Int J Mol Sci Article Breast cancer remains the major cause of cancer-induced morbidity and mortality in women. Among the different molecular subtypes, luminal tumors yet considered of good prognosis often develop acquired resistance to endocrine therapy. Recently, misregulation of ERα36 was reported to play a crucial role in this process. High expression of this ERα isoform was associated to preneoplastic phenotype in mammary epithelial cells, disease progression, and enhanced resistance to therapeutic agents in breast tumors. In this study, we identified two mechanisms that could together contribute to ERα36 expression regulation. We first focused on hsa-miR-136-5p, an ERα36 3’UTR-targeting microRNA, the expression of which inversely correlated to the ERα36 one in breast cancer cells. Transfection of hsa-miR136-5p mimic in MCF-7 cells resulted in downregulation of ERα36. Moreover, the demethylating agent decitabine was able to stimulate hsa-miR-136-5p endogenous expression, thus indirectly decreasing ERα36 expression and counteracting tamoxifen-dependent stimulation. The methylation status of ERα36 promoter also directly modulated its expression level, as demonstrated after decitabine treatment of breast cancer cell and confirmed in a set of tumor samples. Taken together, these results open the way to a direct and an indirect ERα36 epigenetic modulation by decitabine as a promising clinical strategy to counteract acquired resistance to treatment and prevent relapse. MDPI 2019-05-29 /pmc/articles/PMC6600239/ /pubmed/31146345 http://dx.doi.org/10.3390/ijms20112637 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Thiebaut, Charlène
Chesnel, Amand
Merlin, Jean-Louis
Chesnel, Maelle
Leroux, Agnès
Harlé, Alexandre
Dumond, Hélène
Dual Epigenetic Regulation of ERα36 Expression in Breast Cancer Cells
title Dual Epigenetic Regulation of ERα36 Expression in Breast Cancer Cells
title_full Dual Epigenetic Regulation of ERα36 Expression in Breast Cancer Cells
title_fullStr Dual Epigenetic Regulation of ERα36 Expression in Breast Cancer Cells
title_full_unstemmed Dual Epigenetic Regulation of ERα36 Expression in Breast Cancer Cells
title_short Dual Epigenetic Regulation of ERα36 Expression in Breast Cancer Cells
title_sort dual epigenetic regulation of erα36 expression in breast cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600239/
https://www.ncbi.nlm.nih.gov/pubmed/31146345
http://dx.doi.org/10.3390/ijms20112637
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