Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cells

Breast cancer prognosis and response to endocrine therapy strongly depends on the expression of the estrogen and progesterone receptors (ER and PR, respectively). Although much is known about ERα gene (ESR1) regulation after hormonal stimulation, how it is regulated in hormone-free condition is not...

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Autores: Verde, Gaetano, De Llobet, Lara Isabel, Wright, Roni H.G., Quilez Oliete, Javier, Peiró Sales, Sandra, Le Dily, François, Beato, Miguel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/42572
Acceso en línea:http://hdl.handle.net/10230/42572
http://dx.doi.org/10.3390/cancers10100371
Access Level:acceso abierto
Palabra clave:DNA methylation
Breast cancer
Endocrine therapy
Estrogen receptor
Gene expression
Progesterone receptor
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spelling Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cellsVerde, GaetanoDe Llobet, Lara IsabelWright, Roni H.G.Quilez Oliete, JavierPeiró Sales, SandraLe Dily, FrançoisBeato, MiguelDNA methylationBreast cancerEndocrine therapyEstrogen receptorGene expressionProgesterone receptorBreast cancer prognosis and response to endocrine therapy strongly depends on the expression of the estrogen and progesterone receptors (ER and PR, respectively). Although much is known about ERα gene (ESR1) regulation after hormonal stimulation, how it is regulated in hormone-free condition is not fully understood. We used ER-/PR-positive breast cancer cells to investigate the role of PR in ESR1 regulation in the absence of hormones. We show that PR binds to the low-methylated ESR1 promoter and maintains both gene expression and DNA methylation of the ESR1 locus in hormone-deprived breast cancer cells. Depletion of PR reduces ESR1 expression, with a concomitant increase in gene promoter methylation. The high amount of methylation in the ESR1 promoter of PR-depleted cells persists after the stable re-expression of PR and inhibits PR binding to this genomic region. As a consequence, the rescue of PR expression in PR-depleted cells is insufficient to restore ESR1 expression. Consistently, DNA methylation impedes PR binding to consensus progesterone responsive elements. These findings contribute to understanding the complex crosstalk between PR and ER and suggest that the analysis of ESR1 promoter methylation in breast cancer cells can help to design more appropriate targeted therapies for breast cancer patients.We received funding from the Spanish Ministry of Economy and Competitiveness, Plan Nacional Project SAF 2013-42497-P; Centro de Excelencia Severo Ochoa 2013–2017; the Centre de Recerca de Catalunya (CERCA) Programme/Generalitat de Catalunya; G.V. has received funding from the Spanish Ministry of Economy and Competitiveness, “Juan de la Cierva Incorporation” fellowship (Ref. IJCI-2014-20723), the European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreement Number 299429 and the European Molecular Biology Organization (EMBO long-term fellowship ALTF 1106-2011, cofunded with the European Commission EMBOCOFUND2010, GA-2010-267146).MDPI201920192018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/42572http://dx.doi.org/10.3390/cancers10100371reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésCancers (Basel). 2018;10(10):371info:eu-repo/grantAgreement/EC/FP7/299429info:eu-repo/grantAgreement/ES/1PE/SAF2013-42497-P© 2018 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/).http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/425722026-06-12T07:21:37Z
dc.title.none.fl_str_mv Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cells
title Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cells
spellingShingle Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cells
Verde, Gaetano
DNA methylation
Breast cancer
Endocrine therapy
Estrogen receptor
Gene expression
Progesterone receptor
title_short Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cells
title_full Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cells
title_fullStr Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cells
title_full_unstemmed Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cells
title_sort Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cells
dc.creator.none.fl_str_mv Verde, Gaetano
De Llobet, Lara Isabel
Wright, Roni H.G.
Quilez Oliete, Javier
Peiró Sales, Sandra
Le Dily, François
Beato, Miguel
author Verde, Gaetano
author_facet Verde, Gaetano
De Llobet, Lara Isabel
Wright, Roni H.G.
Quilez Oliete, Javier
Peiró Sales, Sandra
Le Dily, François
Beato, Miguel
author_role author
author2 De Llobet, Lara Isabel
Wright, Roni H.G.
Quilez Oliete, Javier
Peiró Sales, Sandra
Le Dily, François
Beato, Miguel
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv DNA methylation
Breast cancer
Endocrine therapy
Estrogen receptor
Gene expression
Progesterone receptor
topic DNA methylation
Breast cancer
Endocrine therapy
Estrogen receptor
Gene expression
Progesterone receptor
description Breast cancer prognosis and response to endocrine therapy strongly depends on the expression of the estrogen and progesterone receptors (ER and PR, respectively). Although much is known about ERα gene (ESR1) regulation after hormonal stimulation, how it is regulated in hormone-free condition is not fully understood. We used ER-/PR-positive breast cancer cells to investigate the role of PR in ESR1 regulation in the absence of hormones. We show that PR binds to the low-methylated ESR1 promoter and maintains both gene expression and DNA methylation of the ESR1 locus in hormone-deprived breast cancer cells. Depletion of PR reduces ESR1 expression, with a concomitant increase in gene promoter methylation. The high amount of methylation in the ESR1 promoter of PR-depleted cells persists after the stable re-expression of PR and inhibits PR binding to this genomic region. As a consequence, the rescue of PR expression in PR-depleted cells is insufficient to restore ESR1 expression. Consistently, DNA methylation impedes PR binding to consensus progesterone responsive elements. These findings contribute to understanding the complex crosstalk between PR and ER and suggest that the analysis of ESR1 promoter methylation in breast cancer cells can help to design more appropriate targeted therapies for breast cancer patients.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/42572
http://dx.doi.org/10.3390/cancers10100371
url http://hdl.handle.net/10230/42572
http://dx.doi.org/10.3390/cancers10100371
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Cancers (Basel). 2018;10(10):371
info:eu-repo/grantAgreement/EC/FP7/299429
info:eu-repo/grantAgreement/ES/1PE/SAF2013-42497-P
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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