BET Proteins Exhibit Transcriptional and Functional Opposition in the Epithelial-to-Mesenchymal Transition
Transcriptional programs in embryogenesis and cancer, such as the epithelial-to-mesenchymal transition (EMT), ensure cellular plasticity, an essential feature of carcinoma progression. As effectors of signal transduction, the bromodomain and extraterminal (BET) proteins are well suited to support pl...
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| Veröffentlicht in: | Molecular cancer research 2018-04, Vol.16 (4), p.580-586 |
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| creator | Andrieu, Guillaume P Denis, Gerald V |
| description | Transcriptional programs in embryogenesis and cancer, such as the epithelial-to-mesenchymal transition (EMT), ensure cellular plasticity, an essential feature of carcinoma progression. As effectors of signal transduction, the bromodomain and extraterminal (BET) proteins are well suited to support plasticity because they function as co-activators or co-repressors of mammalian transcriptomes. Here, using both hormone-sensitive and triple-negative breast cancer (TNBC) model systems, we systematically altered EMT transcriptional profiles by manipulating individual BET proteins and found that BRD2 positively regulates EMT, whereas BRD3 and BRD4 repress this program. Knockdown of individual BET proteins revealed independent transcriptional networks that differed from each other and from the small-molecule pan-BET inhibitor JQ1, which previously had been misleadingly asserted to be BRD4-selective. Available small-molecule pan-BET inhibitors, proposed as antiproliferative agents in cancer clinical trials, obscure these biological differences. Transcriptional profiling reveals that individual BET proteins, inhibited separately, engage in and control EMT through unique processes.
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| doi_str_mv | 10.1158/1541-7786.mcr-17-0568 |
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http://mcr.aacrjournals.org/content/molcanres/16/4/580/F1.large.jpg
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http://mcr.aacrjournals.org/content/molcanres/16/4/580/F1.large.jpg
.</description><subject>Breast cancer</subject><subject>Cancer</subject><subject>Clinical trials</subject><subject>Embryogenesis</subject><subject>Embryonic growth stage</subject><subject>Medical research</subject><subject>Mesenchyme</subject><subject>Plastic foam</subject><subject>Plastic properties</subject><subject>Plasticity</subject><subject>Proteins</subject><subject>Repressors</subject><subject>Signal transduction</subject><subject>Transcription</subject><issn>1541-7786</issn><issn>1557-3125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNpdkU1P3DAQhi3Uiu-fAIrUSy-mYzuOnQsSXS0fEoiqWs6W4zisV4kd7KQq_54EFkR7mhnNM69m5kXohMAZIVz-IDwnWAhZnHUmYiIw8ELuoH3CucCMUP5lzrfMHjpIaQNAgYhiF-3RMmdC8nwfbX4uV9mvGAbrfMqWf9euckO2itonE10_uOB1m2lfZ5ejN9vyvu9DcnOROZ8Na5stezeF1ukWDwHf2WS9WT93E_sq9coeoa-NbpM93sZD9HC5XC2u8e391c3i4habafUBl1Aa3nAqAfIcqqo0dVMTWXJtuKh4TahhtSkkB91IkNI2pJYMcga2aoSx7BCdv-n2Y9XZ2lg_RN2qPrpOx2cVtFP_drxbq8fwR3EpKWcwCXzfCsTwNNo0qM4lY9tWexvGpOj0SEpA5mxCv_2HbsIYpx_NFIUcyoLMgvyNMjGkFG3zsQwBNbupZqfU7JS6W_xWRKjZzWnu9PMlH1Pv9rEXJtWdzQ</recordid><startdate>20180401</startdate><enddate>20180401</enddate><creator>Andrieu, Guillaume P</creator><creator>Denis, Gerald V</creator><general>American Association for Cancer Research Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180401</creationdate><title>BET Proteins Exhibit Transcriptional and Functional Opposition in the Epithelial-to-Mesenchymal Transition</title><author>Andrieu, Guillaume P ; Denis, Gerald V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c557t-909c5f52800440bb9cdfd1895ac57b5d12c3dc6850af8088ef1d830430ebf7ce3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Breast cancer</topic><topic>Cancer</topic><topic>Clinical trials</topic><topic>Embryogenesis</topic><topic>Embryonic growth stage</topic><topic>Medical research</topic><topic>Mesenchyme</topic><topic>Plastic foam</topic><topic>Plastic properties</topic><topic>Plasticity</topic><topic>Proteins</topic><topic>Repressors</topic><topic>Signal transduction</topic><topic>Transcription</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Andrieu, Guillaume P</creatorcontrib><creatorcontrib>Denis, Gerald V</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Andrieu, Guillaume P</au><au>Denis, Gerald V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BET Proteins Exhibit Transcriptional and Functional Opposition in the Epithelial-to-Mesenchymal Transition</atitle><jtitle>Molecular cancer research</jtitle><addtitle>Mol Cancer Res</addtitle><date>2018-04-01</date><risdate>2018</risdate><volume>16</volume><issue>4</issue><spage>580</spage><epage>586</epage><pages>580-586</pages><issn>1541-7786</issn><eissn>1557-3125</eissn><abstract>Transcriptional programs in embryogenesis and cancer, such as the epithelial-to-mesenchymal transition (EMT), ensure cellular plasticity, an essential feature of carcinoma progression. As effectors of signal transduction, the bromodomain and extraterminal (BET) proteins are well suited to support plasticity because they function as co-activators or co-repressors of mammalian transcriptomes. Here, using both hormone-sensitive and triple-negative breast cancer (TNBC) model systems, we systematically altered EMT transcriptional profiles by manipulating individual BET proteins and found that BRD2 positively regulates EMT, whereas BRD3 and BRD4 repress this program. Knockdown of individual BET proteins revealed independent transcriptional networks that differed from each other and from the small-molecule pan-BET inhibitor JQ1, which previously had been misleadingly asserted to be BRD4-selective. Available small-molecule pan-BET inhibitors, proposed as antiproliferative agents in cancer clinical trials, obscure these biological differences. Transcriptional profiling reveals that individual BET proteins, inhibited separately, engage in and control EMT through unique processes.
http://mcr.aacrjournals.org/content/molcanres/16/4/580/F1.large.jpg
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| source | American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Breast cancer Cancer Clinical trials Embryogenesis Embryonic growth stage Medical research Mesenchyme Plastic foam Plastic properties Plasticity Proteins Repressors Signal transduction Transcription |
| title | BET Proteins Exhibit Transcriptional and Functional Opposition in the Epithelial-to-Mesenchymal Transition |
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