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 ( ) regulation after hormonal stimulation, how it is regulated in hormone-free condition is not ful...
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| Veröffentlicht in: | Cancers 2018-10, Vol.10 (10), p.371 |
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| creator | Verde, Gaetano De Llobet, Lara I Wright, Roni H G Quilez, Javier Peiró, Sandra Le Dily, François Beato, Miguel |
| 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 (
) 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
regulation in the absence of hormones. We show that PR binds to the low-methylated
promoter and maintains both gene expression and DNA methylation of the ESR1 locus in hormone-deprived breast cancer cells. Depletion of PR reduces
expression, with a concomitant increase in gene promoter methylation. The high amount of methylation in the
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
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
promoter methylation in breast cancer cells can help to design more appropriate targeted therapies for breast cancer patients. |
| doi_str_mv | 10.3390/cancers10100371 |
| format | Article |
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) 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
regulation in the absence of hormones. We show that PR binds to the low-methylated
promoter and maintains both gene expression and DNA methylation of the ESR1 locus in hormone-deprived breast cancer cells. Depletion of PR reduces
expression, with a concomitant increase in gene promoter methylation. The high amount of methylation in the
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
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
promoter methylation in breast cancer cells can help to design more appropriate targeted therapies for breast cancer patients.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers10100371</identifier><identifier>PMID: 30301163</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Bioinformatics ; Breast cancer ; Cell cycle ; Cloning ; Deoxyribonucleic acid ; DNA ; DNA methylation ; Endocrine therapy ; Estrogen receptor ; Estrogen receptors ; Experiments ; Gene expression ; Genomes ; Growth factors ; Hormones ; Kinases ; Progesterone ; Progesterone receptor ; Progesterone receptors ; Proteins</subject><ispartof>Cancers, 2018-10, Vol.10 (10), p.371</ispartof><rights>2018. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>info:eu-repo/semantics/openAccess © 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 (<a href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</a>). <a href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</a></rights><rights>2018 by the authors. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-b3604a3c73ae2b903b21a0d368a70a790b12c4cf896d754afcb82f5e13c47ac43</citedby><cites>FETCH-LOGICAL-c463t-b3604a3c73ae2b903b21a0d368a70a790b12c4cf896d754afcb82f5e13c47ac43</cites><orcidid>0000-0003-4768-0165 ; 0000-0001-6249-7276 ; 0000-0001-9519-3877 ; 0000-0002-8324-7927 ; 0000-0002-8194-4614</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210734/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210734/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,26951,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30301163$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Verde, Gaetano</creatorcontrib><creatorcontrib>De Llobet, Lara I</creatorcontrib><creatorcontrib>Wright, Roni H G</creatorcontrib><creatorcontrib>Quilez, Javier</creatorcontrib><creatorcontrib>Peiró, Sandra</creatorcontrib><creatorcontrib>Le Dily, François</creatorcontrib><creatorcontrib>Beato, Miguel</creatorcontrib><title>Unliganded Progesterone Receptor Governs Estrogen Receptor Gene Expression by Regulating DNA Methylation in Breast Cancer Cells</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><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 (
) 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
regulation in the absence of hormones. We show that PR binds to the low-methylated
promoter and maintains both gene expression and DNA methylation of the ESR1 locus in hormone-deprived breast cancer cells. Depletion of PR reduces
expression, with a concomitant increase in gene promoter methylation. The high amount of methylation in the
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
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
promoter methylation in breast cancer cells can help to design more appropriate targeted therapies for breast cancer patients.</description><subject>Bioinformatics</subject><subject>Breast cancer</subject><subject>Cell cycle</subject><subject>Cloning</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>Endocrine therapy</subject><subject>Estrogen receptor</subject><subject>Estrogen receptors</subject><subject>Experiments</subject><subject>Gene expression</subject><subject>Genomes</subject><subject>Growth factors</subject><subject>Hormones</subject><subject>Kinases</subject><subject>Progesterone</subject><subject>Progesterone receptor</subject><subject>Progesterone receptors</subject><subject>Proteins</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><sourceid>XX2</sourceid><recordid>eNpdUsFu1DAQtRCIVqVnbsgSFy7b2p6snVyQyrItSKVFiJ4tx5mkqbL2YjsVe-qv12mX1VJLlmf03hvPPA0h7zk7AajYqTXOYoicccZA8VfkUDAlZlJWxeu9-IAcx3jH8gHgSqq35AAYMM4lHJKHGzf0nXENNvRn8B3GhME7pL_Q4jr5QC_8PQYX6TKmCXd7CGbe8u86YIy9d7TeZKwbB5N619GvV2f0B6bbzZRntHf0S0ATE1089U0XOAzxHXnTmiHi8fY9Ijfny9-Lb7PL64vvi7PLmS0kpFkNkhUGrAKDoq4Y1IIb1oAsjWJGVazmwha2LSvZqHlhWluXop0jB1soYws4Ip-f667HeoWNRZeCGfQ69CsTNtqbXv-PuP5Wd_5eS8GZgqkAfy5g42h1yB4Ea9KTcJdMd7Jdg4SqFFnzaftp8H_GbK1e9dHmsY1DP0YtOFdlFnCeqR9fUO_8GFy2JLPEXAgxV2VmnW6bCD7GgO1uAM70tBP6xU5kxYf9uXf8fxsAj7NPtQA</recordid><startdate>20181005</startdate><enddate>20181005</enddate><creator>Verde, Gaetano</creator><creator>De Llobet, Lara I</creator><creator>Wright, Roni H G</creator><creator>Quilez, Javier</creator><creator>Peiró, Sandra</creator><creator>Le Dily, François</creator><creator>Beato, Miguel</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>XX2</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4768-0165</orcidid><orcidid>https://orcid.org/0000-0001-6249-7276</orcidid><orcidid>https://orcid.org/0000-0001-9519-3877</orcidid><orcidid>https://orcid.org/0000-0002-8324-7927</orcidid><orcidid>https://orcid.org/0000-0002-8194-4614</orcidid></search><sort><creationdate>20181005</creationdate><title>Unliganded Progesterone Receptor Governs Estrogen Receptor Gene Expression by Regulating DNA Methylation in Breast Cancer Cells</title><author>Verde, Gaetano ; De Llobet, Lara I ; Wright, Roni H G ; Quilez, Javier ; Peiró, Sandra ; Le Dily, François ; Beato, Miguel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-b3604a3c73ae2b903b21a0d368a70a790b12c4cf896d754afcb82f5e13c47ac43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Bioinformatics</topic><topic>Breast cancer</topic><topic>Cell cycle</topic><topic>Cloning</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA methylation</topic><topic>Endocrine therapy</topic><topic>Estrogen receptor</topic><topic>Estrogen receptors</topic><topic>Experiments</topic><topic>Gene expression</topic><topic>Genomes</topic><topic>Growth factors</topic><topic>Hormones</topic><topic>Kinases</topic><topic>Progesterone</topic><topic>Progesterone receptor</topic><topic>Progesterone receptors</topic><topic>Proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Verde, Gaetano</creatorcontrib><creatorcontrib>De Llobet, Lara I</creatorcontrib><creatorcontrib>Wright, Roni H G</creatorcontrib><creatorcontrib>Quilez, Javier</creatorcontrib><creatorcontrib>Peiró, Sandra</creatorcontrib><creatorcontrib>Le Dily, François</creatorcontrib><creatorcontrib>Beato, Miguel</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>Recercat</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Verde, Gaetano</au><au>De Llobet, Lara I</au><au>Wright, Roni H G</au><au>Quilez, Javier</au><au>Peiró, Sandra</au><au>Le Dily, François</au><au>Beato, Miguel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Unliganded Progesterone Receptor Governs Estrogen Receptor Gene Expression by Regulating DNA Methylation in Breast Cancer Cells</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2018-10-05</date><risdate>2018</risdate><volume>10</volume><issue>10</issue><spage>371</spage><pages>371-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><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 (
) 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
regulation in the absence of hormones. We show that PR binds to the low-methylated
promoter and maintains both gene expression and DNA methylation of the ESR1 locus in hormone-deprived breast cancer cells. Depletion of PR reduces
expression, with a concomitant increase in gene promoter methylation. The high amount of methylation in the
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
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
promoter methylation in breast cancer cells can help to design more appropriate targeted therapies for breast cancer patients.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>30301163</pmid><doi>10.3390/cancers10100371</doi><orcidid>https://orcid.org/0000-0003-4768-0165</orcidid><orcidid>https://orcid.org/0000-0001-6249-7276</orcidid><orcidid>https://orcid.org/0000-0001-9519-3877</orcidid><orcidid>https://orcid.org/0000-0002-8324-7927</orcidid><orcidid>https://orcid.org/0000-0002-8194-4614</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; Recercat; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access |
| subjects | Bioinformatics Breast cancer Cell cycle Cloning Deoxyribonucleic acid DNA DNA methylation Endocrine therapy Estrogen receptor Estrogen receptors Experiments Gene expression Genomes Growth factors Hormones Kinases Progesterone Progesterone receptor Progesterone receptors Proteins |
| title | Unliganded Progesterone Receptor Governs Estrogen Receptor Gene Expression by Regulating DNA Methylation in Breast Cancer Cells |
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