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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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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. |
format | Online Article Text |
id | pubmed-6600239 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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