Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3
Abstract Estrogen receptors (ER) are activated by the steroid hormone 17β-estradiol. Estrogen receptor alpha (ER-α) forms a regulatory network in mammary epithelial cells and in breast cancer with the transcription factors FOXA1 and GATA3. GATA3 is one of the most frequently mutated genes in breast...
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Veröffentlicht in: | Nucleic acids research 2020-05, Vol.48 (9), p.4756-4768 |
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creator | Takaku, Motoki Grimm, Sara A De Kumar, Bony Bennett, Brian D Wade, Paul A |
description | Abstract
Estrogen receptors (ER) are activated by the steroid hormone 17β-estradiol. Estrogen receptor alpha (ER-α) forms a regulatory network in mammary epithelial cells and in breast cancer with the transcription factors FOXA1 and GATA3. GATA3 is one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER-α. How GATA3 mutations found in breast cancer impact genomic localization of ER-α and the transcriptional network downstream of ER-α and FOXA1 remains unclear. Here, we investigate the function of a recurrent patient-derived GATA3 mutation (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt localization of ER-α and FOXA1. Loci co-bound by all three factors are enriched for genes integral to mammary gland development as well as epithelial cell biology. This gene set is differentially regulated in GATA3 mutant cells in culture and in tumors bearing similar mutations in vivo. The altered distribution of ER-α and FOXA1 in GATA3-mutant cells is associated with altered chromatin architecture, which leads to differential gene expression. These results suggest an active role for GATA3 zinc finger 2 mutants in ER-α positive breast tumors. |
doi_str_mv | 10.1093/nar/gkaa179 |
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Estrogen receptors (ER) are activated by the steroid hormone 17β-estradiol. Estrogen receptor alpha (ER-α) forms a regulatory network in mammary epithelial cells and in breast cancer with the transcription factors FOXA1 and GATA3. GATA3 is one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER-α. How GATA3 mutations found in breast cancer impact genomic localization of ER-α and the transcriptional network downstream of ER-α and FOXA1 remains unclear. Here, we investigate the function of a recurrent patient-derived GATA3 mutation (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt localization of ER-α and FOXA1. Loci co-bound by all three factors are enriched for genes integral to mammary gland development as well as epithelial cell biology. This gene set is differentially regulated in GATA3 mutant cells in culture and in tumors bearing similar mutations in vivo. The altered distribution of ER-α and FOXA1 in GATA3-mutant cells is associated with altered chromatin architecture, which leads to differential gene expression. These results suggest an active role for GATA3 zinc finger 2 mutants in ER-α positive breast tumors.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkaa179</identifier><identifier>PMID: 32232341</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Gene regulation, Chromatin and Epigenetics</subject><ispartof>Nucleic acids research, 2020-05, Vol.48 (9), p.4756-4768</ispartof><rights>Published by Oxford University Press on behalf of Nucleic Acids Research 2020. 2020</rights><rights>Published by Oxford University Press on behalf of Nucleic Acids Research 2020.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c478t-545ed2c37953df248b262e419e3a415c7579a009e954203feb2e1dc0408aa7793</citedby><cites>FETCH-LOGICAL-c478t-545ed2c37953df248b262e419e3a415c7579a009e954203feb2e1dc0408aa7793</cites><orcidid>0000-0002-6042-357X</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/PMC7229857/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229857/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1604,27924,27925,53791,53793</link.rule.ids><linktorsrc>$$Uhttps://dx.doi.org/10.1093/nar/gkaa179$$EView_record_in_Oxford_University_Press$$FView_record_in_$$GOxford_University_Press</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32232341$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Takaku, Motoki</creatorcontrib><creatorcontrib>Grimm, Sara A</creatorcontrib><creatorcontrib>De Kumar, Bony</creatorcontrib><creatorcontrib>Bennett, Brian D</creatorcontrib><creatorcontrib>Wade, Paul A</creatorcontrib><title>Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Abstract
Estrogen receptors (ER) are activated by the steroid hormone 17β-estradiol. Estrogen receptor alpha (ER-α) forms a regulatory network in mammary epithelial cells and in breast cancer with the transcription factors FOXA1 and GATA3. GATA3 is one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER-α. How GATA3 mutations found in breast cancer impact genomic localization of ER-α and the transcriptional network downstream of ER-α and FOXA1 remains unclear. Here, we investigate the function of a recurrent patient-derived GATA3 mutation (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt localization of ER-α and FOXA1. Loci co-bound by all three factors are enriched for genes integral to mammary gland development as well as epithelial cell biology. This gene set is differentially regulated in GATA3 mutant cells in culture and in tumors bearing similar mutations in vivo. The altered distribution of ER-α and FOXA1 in GATA3-mutant cells is associated with altered chromatin architecture, which leads to differential gene expression. These results suggest an active role for GATA3 zinc finger 2 mutants in ER-α positive breast tumors.</description><subject>Gene regulation, Chromatin and Epigenetics</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kUtLI0EUhQtx0PhYuZdauRl7rFenujZCCPEBQmBwwF1zU307ae1UNVXVSv7A_G47RMXZzOou7nfP4dxDyBlnvzgz8spBuFq-AHBt9siIy7HIlBmLfTJikuUZZ6o4JEcxPjPGFc_VATmUQkghFR-Rv1NwFkMWO7RN3Vi67hOkxjvqa3o7eZxIWjUx9F2KNK2QpgAu2tB0WwZaGnDZt5B82FCH6c2HF7r0rxgcVnSxobOYgl-io7_RYjdgFNpuBZf0Zv404RRctTM5IT9qaCOefsxj8udm9ji9yx7mt_fTyUNmlS5SlqscK2GlNrmsaqGKhRgLVNyghCGa1bk2wJhBkyvBZI0LgbyyTLECQGsjj8n1TrfrF2usLLohUFt2oVlD2JQemvLfjWtW5RCo1EKYIteDwM-dgA0-xoD11y1n5baOcqij_KhjoM-_232xn_8fgIsd4Pvuv0rv1VKWUA</recordid><startdate>20200521</startdate><enddate>20200521</enddate><creator>Takaku, Motoki</creator><creator>Grimm, Sara A</creator><creator>De Kumar, Bony</creator><creator>Bennett, Brian D</creator><creator>Wade, Paul A</creator><general>Oxford University Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6042-357X</orcidid></search><sort><creationdate>20200521</creationdate><title>Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3</title><author>Takaku, Motoki ; Grimm, Sara A ; De Kumar, Bony ; Bennett, Brian D ; Wade, Paul A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-545ed2c37953df248b262e419e3a415c7579a009e954203feb2e1dc0408aa7793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Gene regulation, Chromatin and Epigenetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takaku, Motoki</creatorcontrib><creatorcontrib>Grimm, Sara A</creatorcontrib><creatorcontrib>De Kumar, Bony</creatorcontrib><creatorcontrib>Bennett, Brian D</creatorcontrib><creatorcontrib>Wade, Paul A</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Takaku, Motoki</au><au>Grimm, Sara A</au><au>De Kumar, Bony</au><au>Bennett, Brian D</au><au>Wade, Paul A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2020-05-21</date><risdate>2020</risdate><volume>48</volume><issue>9</issue><spage>4756</spage><epage>4768</epage><pages>4756-4768</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Abstract
Estrogen receptors (ER) are activated by the steroid hormone 17β-estradiol. Estrogen receptor alpha (ER-α) forms a regulatory network in mammary epithelial cells and in breast cancer with the transcription factors FOXA1 and GATA3. GATA3 is one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER-α. How GATA3 mutations found in breast cancer impact genomic localization of ER-α and the transcriptional network downstream of ER-α and FOXA1 remains unclear. Here, we investigate the function of a recurrent patient-derived GATA3 mutation (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt localization of ER-α and FOXA1. Loci co-bound by all three factors are enriched for genes integral to mammary gland development as well as epithelial cell biology. This gene set is differentially regulated in GATA3 mutant cells in culture and in tumors bearing similar mutations in vivo. The altered distribution of ER-α and FOXA1 in GATA3-mutant cells is associated with altered chromatin architecture, which leads to differential gene expression. These results suggest an active role for GATA3 zinc finger 2 mutants in ER-α positive breast tumors.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>32232341</pmid><doi>10.1093/nar/gkaa179</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-6042-357X</orcidid><oa>free_for_read</oa></addata></record> |
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title | Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3 |
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