DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer
Expression of oestrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy, but does not guarantee patient response. The molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here we characterize the DNA...
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| Veröffentlicht in: | Nature communications 2015-07, Vol.6 (1), p.7758-7758, Article 7758 |
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| creator | Stone, Andrew Zotenko, Elena Locke, Warwick J. Korbie, Darren Millar, Ewan K. A. Pidsley, Ruth Stirzaker, Clare Graham, Peter Trau, Matt Musgrove, Elizabeth A. Nicholson, Robert I. Gee, Julia M. W. Clark, Susan J. |
| description | Expression of oestrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy, but does not guarantee patient response. The molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at oestrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1 activity, thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine-responsive ESR1-positive cancer. Cumulatively, these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy.
The molecular factors influencing patient response to endocrine therapy are poorly understood. Here Stone
et al.
characterize the DNA methylome of endocrine response and show that methylation of oestrogen receptor-associated enhancers underpins endocrine sensitivity in human breast cancer. |
| doi_str_mv | 10.1038/ncomms8758 |
| format | Article |
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The molecular factors influencing patient response to endocrine therapy are poorly understood. Here Stone
et al.
characterize the DNA methylome of endocrine response and show that methylation of oestrogen receptor-associated enhancers underpins endocrine sensitivity in human breast cancer.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/ncomms8758</identifier><identifier>PMID: 26169690</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/208/176/1988 ; 631/208/199 ; 692/699/67/1059 ; 692/699/67/1347 ; Adult ; Aged ; Antineoplastic Agents, Hormonal - therapeutic use ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Carcinoma, Ductal, Breast - drug therapy ; Carcinoma, Ductal, Breast - genetics ; Carcinoma, Ductal, Breast - metabolism ; Carcinoma, Lobular - drug therapy ; Carcinoma, Lobular - genetics ; Carcinoma, Lobular - metabolism ; Chromatin Immunoprecipitation ; DNA Methylation - genetics ; Drug Resistance, Neoplasm - genetics ; Enhancer Elements, Genetic - genetics ; Estrogen Receptor alpha - genetics ; Estrogen Receptor alpha - metabolism ; Female ; Humanities and Social Sciences ; Humans ; MCF-7 Cells ; Middle Aged ; multidisciplinary ; Multiplex Polymerase Chain Reaction ; Science ; Science (multidisciplinary) ; Tamoxifen - therapeutic use</subject><ispartof>Nature communications, 2015-07, Vol.6 (1), p.7758-7758, Article 7758</ispartof><rights>The Author(s) 2015</rights><rights>Copyright Nature Publishing Group Jul 2015</rights><rights>Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2015 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-f08b310bf5b66cb3465be5f231541887f72c22e31de28b34e6137141fd9384b43</citedby><cites>FETCH-LOGICAL-c442t-f08b310bf5b66cb3465be5f231541887f72c22e31de28b34e6137141fd9384b43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510968/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510968/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51554,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26169690$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Stone, Andrew</creatorcontrib><creatorcontrib>Zotenko, Elena</creatorcontrib><creatorcontrib>Locke, Warwick J.</creatorcontrib><creatorcontrib>Korbie, Darren</creatorcontrib><creatorcontrib>Millar, Ewan K. A.</creatorcontrib><creatorcontrib>Pidsley, Ruth</creatorcontrib><creatorcontrib>Stirzaker, Clare</creatorcontrib><creatorcontrib>Graham, Peter</creatorcontrib><creatorcontrib>Trau, Matt</creatorcontrib><creatorcontrib>Musgrove, Elizabeth A.</creatorcontrib><creatorcontrib>Nicholson, Robert I.</creatorcontrib><creatorcontrib>Gee, Julia M. W.</creatorcontrib><creatorcontrib>Clark, Susan J.</creatorcontrib><title>DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>Expression of oestrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy, but does not guarantee patient response. The molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at oestrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1 activity, thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine-responsive ESR1-positive cancer. Cumulatively, these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy.
The molecular factors influencing patient response to endocrine therapy are poorly understood. Here Stone
et al.
characterize the DNA methylome of endocrine response and show that methylation of oestrogen receptor-associated enhancers underpins endocrine sensitivity in human breast cancer.</description><subject>631/208/176/1988</subject><subject>631/208/199</subject><subject>692/699/67/1059</subject><subject>692/699/67/1347</subject><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic Agents, Hormonal - therapeutic use</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Carcinoma, Ductal, Breast - drug therapy</subject><subject>Carcinoma, Ductal, Breast - genetics</subject><subject>Carcinoma, Ductal, Breast - metabolism</subject><subject>Carcinoma, Lobular - drug therapy</subject><subject>Carcinoma, Lobular - genetics</subject><subject>Carcinoma, Lobular - metabolism</subject><subject>Chromatin Immunoprecipitation</subject><subject>DNA Methylation - genetics</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Enhancer Elements, Genetic - genetics</subject><subject>Estrogen Receptor alpha - genetics</subject><subject>Estrogen Receptor alpha - metabolism</subject><subject>Female</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>MCF-7 Cells</subject><subject>Middle Aged</subject><subject>multidisciplinary</subject><subject>Multiplex Polymerase Chain Reaction</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Tamoxifen - therapeutic use</subject><issn>2041-1723</issn><issn>2041-1723</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNplkU1rGzEQhkVoaIyTS39AEORSEjbV1-5qL4Xg5gtCemnPYlc7shV2JVfaNfjfV44dx23mMsPMw6vRvAh9oeSaEi6_Oe37Psoyl0dowoigGS0Z_3RQn6CzGF9ICl5RKcRndMIKWlRFRSZI_Xi-wT0Mi3VXD9Y77A32EIfg5-CyAPMx9aHF4Ba10xAibsFYBzF1Wq9DKnEEF-1gV3ZYY-twE6COA9av_Ck6NnUX4WyXp-j33e2v2UP29PP-cXbzlGkh2JAZIhtOSWPypih0w0WRN5AbxmkuqJSlKZlmDDhtgSVSQEF5SQU1bcWlaASfou9b3eXY9NBqcEOoO7UMtq_DWvnaqn8nzi7U3K-UyCmpCpkEvu4Egv8zpguo3kYNXVc78GNUm4MlTJQb9OI_9MWPwaXvvVKEVSJZM0WXW0oHH2MAs1-GErWxTr1bl-Dzw_X36JtRCbjaAjGN3BzCwZsf5f4CNselQg</recordid><startdate>20150714</startdate><enddate>20150714</enddate><creator>Stone, Andrew</creator><creator>Zotenko, Elena</creator><creator>Locke, Warwick J.</creator><creator>Korbie, Darren</creator><creator>Millar, Ewan K. 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A.</au><au>Pidsley, Ruth</au><au>Stirzaker, Clare</au><au>Graham, Peter</au><au>Trau, Matt</au><au>Musgrove, Elizabeth A.</au><au>Nicholson, Robert I.</au><au>Gee, Julia M. W.</au><au>Clark, Susan J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2015-07-14</date><risdate>2015</risdate><volume>6</volume><issue>1</issue><spage>7758</spage><epage>7758</epage><pages>7758-7758</pages><artnum>7758</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>Expression of oestrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy, but does not guarantee patient response. The molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at oestrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1 activity, thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine-responsive ESR1-positive cancer. Cumulatively, these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy.
The molecular factors influencing patient response to endocrine therapy are poorly understood. Here Stone
et al.
characterize the DNA methylome of endocrine response and show that methylation of oestrogen receptor-associated enhancers underpins endocrine sensitivity in human breast cancer.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>26169690</pmid><doi>10.1038/ncomms8758</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/208/176/1988 631/208/199 692/699/67/1059 692/699/67/1347 Adult Aged Antineoplastic Agents, Hormonal - therapeutic use Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Carcinoma, Ductal, Breast - drug therapy Carcinoma, Ductal, Breast - genetics Carcinoma, Ductal, Breast - metabolism Carcinoma, Lobular - drug therapy Carcinoma, Lobular - genetics Carcinoma, Lobular - metabolism Chromatin Immunoprecipitation DNA Methylation - genetics Drug Resistance, Neoplasm - genetics Enhancer Elements, Genetic - genetics Estrogen Receptor alpha - genetics Estrogen Receptor alpha - metabolism Female Humanities and Social Sciences Humans MCF-7 Cells Middle Aged multidisciplinary Multiplex Polymerase Chain Reaction Science Science (multidisciplinary) Tamoxifen - therapeutic use |
| title | DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer |
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