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

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  • dc.contributor.author Verde, Gaetano
  • dc.contributor.author De Llobet, Lara Isabel
  • dc.contributor.author Wright, Roni H.G.
  • dc.contributor.author Quilez Oliete, Javier
  • dc.contributor.author Peiró Sales, Sandra
  • dc.contributor.author Le Dily, François
  • dc.contributor.author Beato, Miguel
  • dc.date.accessioned 2019-10-31T08:41:32Z
  • dc.date.available 2019-10-31T08:41:32Z
  • dc.date.issued 2018
  • dc.description.abstract 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.
  • dc.description.sponsorship 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).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Verde G, De Llobet LI, Wright RHG, Quilez J, Peiró S, Le Dily F et al. Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cells. Cancers (Basel). 2018;10(10):371. DOI: 10.3390/cancers10100371
  • dc.identifier.doi http://dx.doi.org/10.3390/cancers10100371
  • dc.identifier.issn 2072-6694
  • dc.identifier.uri http://hdl.handle.net/10230/42572
  • dc.language.iso eng
  • dc.publisher MDPI
  • dc.relation.ispartof Cancers (Basel). 2018;10(10):371
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/299429
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-42497-P
  • dc.rights © 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/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword DNA methylation
  • dc.subject.keyword Breast cancer
  • dc.subject.keyword Endocrine therapy
  • dc.subject.keyword Estrogen receptor
  • dc.subject.keyword Gene expression
  • dc.subject.keyword Progesterone receptor
  • dc.title Unliganded progesterone receptor governs estrogen receptor gene expression by regulating DNA methylation in breast cancer cells
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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