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ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer
Antiestrogen resistance is a major obstacle to endocrine therapy for breast cancers. Although reduced estrogen receptor-α (ER-α) expression is a known contributing factor to antiestrogen resistance, the mechanisms of ER-α downregulation in antiestrogen resistance are not fully understood. Here, we r...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477580/ https://www.ncbi.nlm.nih.gov/pubmed/28383555 http://dx.doi.org/10.1038/cddis.2017.154 |
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author | Zhang, Jianbo Zhou, Chen Jiang, Huimin Liang, Lin Shi, Wen Zhang, Quansheng Sun, Peiqing Xiang, Rong Wang, Yue Yang, Shuang |
author_facet | Zhang, Jianbo Zhou, Chen Jiang, Huimin Liang, Lin Shi, Wen Zhang, Quansheng Sun, Peiqing Xiang, Rong Wang, Yue Yang, Shuang |
author_sort | Zhang, Jianbo |
collection | PubMed |
description | Antiestrogen resistance is a major obstacle to endocrine therapy for breast cancers. Although reduced estrogen receptor-α (ER-α) expression is a known contributing factor to antiestrogen resistance, the mechanisms of ER-α downregulation in antiestrogen resistance are not fully understood. Here, we report that ectopic zinc-finger E-box binding homeobox 1 (ZEB1) is associated with ER-α deficiency in breast cancer cells and thus confers antiestrogen resistance. Mechanistically, ZEB1 represses ER-α transcription by forming a ZEB1/DNA methyltransferase (DNMT)3B/histone deacetylase (HDAC)1 complex on the ER-α promoter, leading to DNA hypermethylation and the silencing of ER-α. Thus, ectopic ZEB1 downregulates ER-α expression and subsequently attenuates cell growth inhibition by antiestrogens, such as tamoxifen and fulvestrant. Notably, the depletion of ZEB1 by RNA interference causes ER-α promoter demethylation, restores ER-α expression, and increases the responsiveness of breast cancer cells to antiestrogen treatment. By studying specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between ZEB1 and ER-α protein expression. Moreover, breast tumors that highly express ZEB1 exhibit ER-α promoter hypermethylation. Using a nude mouse xenograft model, we further confirmed that the downregulation of ZEB1 expression restores the responsiveness of breast cancer cells to antiestrogen therapy in vivo. Therefore, our findings suggest that ZEB1 is a crucial determinant of resistance to antiestrogen therapies in breast cancer. |
format | Online Article Text |
id | pubmed-5477580 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-54775802017-07-03 ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer Zhang, Jianbo Zhou, Chen Jiang, Huimin Liang, Lin Shi, Wen Zhang, Quansheng Sun, Peiqing Xiang, Rong Wang, Yue Yang, Shuang Cell Death Dis Original Article Antiestrogen resistance is a major obstacle to endocrine therapy for breast cancers. Although reduced estrogen receptor-α (ER-α) expression is a known contributing factor to antiestrogen resistance, the mechanisms of ER-α downregulation in antiestrogen resistance are not fully understood. Here, we report that ectopic zinc-finger E-box binding homeobox 1 (ZEB1) is associated with ER-α deficiency in breast cancer cells and thus confers antiestrogen resistance. Mechanistically, ZEB1 represses ER-α transcription by forming a ZEB1/DNA methyltransferase (DNMT)3B/histone deacetylase (HDAC)1 complex on the ER-α promoter, leading to DNA hypermethylation and the silencing of ER-α. Thus, ectopic ZEB1 downregulates ER-α expression and subsequently attenuates cell growth inhibition by antiestrogens, such as tamoxifen and fulvestrant. Notably, the depletion of ZEB1 by RNA interference causes ER-α promoter demethylation, restores ER-α expression, and increases the responsiveness of breast cancer cells to antiestrogen treatment. By studying specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between ZEB1 and ER-α protein expression. Moreover, breast tumors that highly express ZEB1 exhibit ER-α promoter hypermethylation. Using a nude mouse xenograft model, we further confirmed that the downregulation of ZEB1 expression restores the responsiveness of breast cancer cells to antiestrogen therapy in vivo. Therefore, our findings suggest that ZEB1 is a crucial determinant of resistance to antiestrogen therapies in breast cancer. Nature Publishing Group 2017-04 2017-04-06 /pmc/articles/PMC5477580/ /pubmed/28383555 http://dx.doi.org/10.1038/cddis.2017.154 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Zhang, Jianbo Zhou, Chen Jiang, Huimin Liang, Lin Shi, Wen Zhang, Quansheng Sun, Peiqing Xiang, Rong Wang, Yue Yang, Shuang ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer |
title | ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer |
title_full | ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer |
title_fullStr | ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer |
title_full_unstemmed | ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer |
title_short | ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer |
title_sort | zeb1 induces er-α promoter hypermethylation and confers antiestrogen resistance in breast cancer |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477580/ https://www.ncbi.nlm.nih.gov/pubmed/28383555 http://dx.doi.org/10.1038/cddis.2017.154 |
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