EN1 Is a Transcriptional Dependency in Triple-Negative Breast Cancer Associated with Brain Metastasis
To define transcriptional dependencies of triple-negative breast cancer (TNBC), we identified transcription factors highly and specifically expressed in primary TNBCs and tested their requirement for cell growth in a panel of breast cancer cell lines. We found that (engrailed 1) is overexpressed in...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2019-08, Vol.79 (16), p.4173-4183 |
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| creator | Peluffo, Guillermo Subedee, Ashim Harper, Nicholas W Kingston, Natalie Jovanović, Bojana Flores, Felipe Stevens, Laura E Beca, Francisco Trinh, Anne Chilamakuri, Chandra Sekhar Reddy Papachristou, Evangelia K Murphy, Katherine Su, Ying Marusyk, Andriy D'Santos, Clive S Rueda, Oscar M Beck, Andrew H Caldas, Carlos Carroll, Jason S Polyak, Kornelia |
| description | To define transcriptional dependencies of triple-negative breast cancer (TNBC), we identified transcription factors highly and specifically expressed in primary TNBCs and tested their requirement for cell growth in a panel of breast cancer cell lines. We found that
(engrailed 1) is overexpressed in TNBCs and its downregulation preferentially and significantly reduced viability and tumorigenicity in TNBC cell lines. By integrating gene expression changes after EN1 downregulation with EN1 chromatin binding patterns, we identified genes involved in WNT and Hedgehog signaling, neurogenesis, and axonal guidance as direct EN1 transcriptional targets. Quantitative proteomic analyses of EN1-bound chromatin complexes revealed association with transcriptional repressors and coactivators including TLE3, TRIM24, TRIM28, and TRIM33. High expression of
correlated with short overall survival and increased risk of developing brain metastases in patients with TNBC. Thus, EN1 is a prognostic marker and a potential therapeutic target in TNBC. SIGNIFICANCE: These findings show that the EN1 transcription factor regulates neurogenesis-related genes and is associated with brain metastasis in triple-negative breast cancer. |
| doi_str_mv | 10.1158/0008-5472.CAN-18-3264 |
| format | Article |
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(engrailed 1) is overexpressed in TNBCs and its downregulation preferentially and significantly reduced viability and tumorigenicity in TNBC cell lines. By integrating gene expression changes after EN1 downregulation with EN1 chromatin binding patterns, we identified genes involved in WNT and Hedgehog signaling, neurogenesis, and axonal guidance as direct EN1 transcriptional targets. Quantitative proteomic analyses of EN1-bound chromatin complexes revealed association with transcriptional repressors and coactivators including TLE3, TRIM24, TRIM28, and TRIM33. High expression of
correlated with short overall survival and increased risk of developing brain metastases in patients with TNBC. Thus, EN1 is a prognostic marker and a potential therapeutic target in TNBC. SIGNIFICANCE: These findings show that the EN1 transcription factor regulates neurogenesis-related genes and is associated with brain metastasis in triple-negative breast cancer.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-18-3264</identifier><identifier>PMID: 31239270</identifier><language>eng</language><publisher>United States</publisher><subject>Brain Neoplasms - genetics ; Brain Neoplasms - mortality ; Brain Neoplasms - secondary ; Co-Repressor Proteins - genetics ; Co-Repressor Proteins - metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Homeodomain Proteins - genetics ; Humans ; MCF-7 Cells ; Prognosis ; Transcription Factors - genetics ; Triple Negative Breast Neoplasms - genetics ; Triple Negative Breast Neoplasms - mortality ; Triple Negative Breast Neoplasms - pathology ; Xenograft Model Antitumor Assays</subject><ispartof>Cancer research (Chicago, Ill.), 2019-08, Vol.79 (16), p.4173-4183</ispartof><rights>2019 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-c1f807f872656bd69ba46046c024ba2c193c3793dd7fa2f59a7f28ea2e6788b3</citedby><cites>FETCH-LOGICAL-c463t-c1f807f872656bd69ba46046c024ba2c193c3793dd7fa2f59a7f28ea2e6788b3</cites><orcidid>0000-0002-4409-012X ; 0000-0002-5835-2055 ; 0000-0003-0008-4884 ; 0000-0002-4037-7473 ; 0000-0002-5962-9896</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,3343,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31239270$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Peluffo, Guillermo</creatorcontrib><creatorcontrib>Subedee, Ashim</creatorcontrib><creatorcontrib>Harper, Nicholas W</creatorcontrib><creatorcontrib>Kingston, Natalie</creatorcontrib><creatorcontrib>Jovanović, Bojana</creatorcontrib><creatorcontrib>Flores, Felipe</creatorcontrib><creatorcontrib>Stevens, Laura E</creatorcontrib><creatorcontrib>Beca, Francisco</creatorcontrib><creatorcontrib>Trinh, Anne</creatorcontrib><creatorcontrib>Chilamakuri, Chandra Sekhar Reddy</creatorcontrib><creatorcontrib>Papachristou, Evangelia K</creatorcontrib><creatorcontrib>Murphy, Katherine</creatorcontrib><creatorcontrib>Su, Ying</creatorcontrib><creatorcontrib>Marusyk, Andriy</creatorcontrib><creatorcontrib>D'Santos, Clive S</creatorcontrib><creatorcontrib>Rueda, Oscar M</creatorcontrib><creatorcontrib>Beck, Andrew H</creatorcontrib><creatorcontrib>Caldas, Carlos</creatorcontrib><creatorcontrib>Carroll, Jason S</creatorcontrib><creatorcontrib>Polyak, Kornelia</creatorcontrib><title>EN1 Is a Transcriptional Dependency in Triple-Negative Breast Cancer Associated with Brain Metastasis</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>To define transcriptional dependencies of triple-negative breast cancer (TNBC), we identified transcription factors highly and specifically expressed in primary TNBCs and tested their requirement for cell growth in a panel of breast cancer cell lines. We found that
(engrailed 1) is overexpressed in TNBCs and its downregulation preferentially and significantly reduced viability and tumorigenicity in TNBC cell lines. By integrating gene expression changes after EN1 downregulation with EN1 chromatin binding patterns, we identified genes involved in WNT and Hedgehog signaling, neurogenesis, and axonal guidance as direct EN1 transcriptional targets. Quantitative proteomic analyses of EN1-bound chromatin complexes revealed association with transcriptional repressors and coactivators including TLE3, TRIM24, TRIM28, and TRIM33. High expression of
correlated with short overall survival and increased risk of developing brain metastases in patients with TNBC. Thus, EN1 is a prognostic marker and a potential therapeutic target in TNBC. SIGNIFICANCE: These findings show that the EN1 transcription factor regulates neurogenesis-related genes and is associated with brain metastasis in triple-negative breast cancer.</description><subject>Brain Neoplasms - genetics</subject><subject>Brain Neoplasms - mortality</subject><subject>Brain Neoplasms - secondary</subject><subject>Co-Repressor Proteins - genetics</subject><subject>Co-Repressor Proteins - metabolism</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Homeodomain Proteins - genetics</subject><subject>Humans</subject><subject>MCF-7 Cells</subject><subject>Prognosis</subject><subject>Transcription Factors - genetics</subject><subject>Triple Negative Breast Neoplasms - genetics</subject><subject>Triple Negative Breast Neoplasms - mortality</subject><subject>Triple Negative Breast Neoplasms - pathology</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1v1DAQtRAV3RZ-AshHLin-tnNBWpa2VCrLZe_WxJm0Rlkn2Nmi_vsmalnR02j0Pmb0HiEfObvgXLsvjDFXaWXFxWa9rbirpDDqDVlxLV1lldJvyerIOSVnpfyeV82ZfkdOJReyFpatCF5uOb0pFOguQyohx3GKQ4KefscRU4spPNKYZjSOPVZbvIMpPiD9lhHKRDeQAma6LmUIESZs6d843c8ozJqfOM0cKLG8Jycd9AU_vMxzsru63G1-VLe_rm8269sqKCOnKvDOMds5K4w2TWvqBpRhygQmVAMi8FoGaWvZtrYD0ekabCccgkBjnWvkOfn6bDsemj22AdOUofdjjnvIj36A6F8jKd77u-HBG1M7IcRs8PnFIA9_Dlgmv48lYN9DwuFQvBBWC2W4Xaj6mRryUErG7niGM7805Jf0_ZK-nxvy3PmloVn36f8fj6p_lcgndd-Nug</recordid><startdate>20190815</startdate><enddate>20190815</enddate><creator>Peluffo, Guillermo</creator><creator>Subedee, Ashim</creator><creator>Harper, Nicholas W</creator><creator>Kingston, Natalie</creator><creator>Jovanović, Bojana</creator><creator>Flores, Felipe</creator><creator>Stevens, Laura E</creator><creator>Beca, Francisco</creator><creator>Trinh, Anne</creator><creator>Chilamakuri, Chandra Sekhar Reddy</creator><creator>Papachristou, Evangelia K</creator><creator>Murphy, Katherine</creator><creator>Su, Ying</creator><creator>Marusyk, Andriy</creator><creator>D'Santos, Clive S</creator><creator>Rueda, Oscar M</creator><creator>Beck, Andrew H</creator><creator>Caldas, Carlos</creator><creator>Carroll, Jason S</creator><creator>Polyak, Kornelia</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4409-012X</orcidid><orcidid>https://orcid.org/0000-0002-5835-2055</orcidid><orcidid>https://orcid.org/0000-0003-0008-4884</orcidid><orcidid>https://orcid.org/0000-0002-4037-7473</orcidid><orcidid>https://orcid.org/0000-0002-5962-9896</orcidid></search><sort><creationdate>20190815</creationdate><title>EN1 Is a Transcriptional Dependency in Triple-Negative Breast Cancer Associated with Brain Metastasis</title><author>Peluffo, Guillermo ; 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We found that
(engrailed 1) is overexpressed in TNBCs and its downregulation preferentially and significantly reduced viability and tumorigenicity in TNBC cell lines. By integrating gene expression changes after EN1 downregulation with EN1 chromatin binding patterns, we identified genes involved in WNT and Hedgehog signaling, neurogenesis, and axonal guidance as direct EN1 transcriptional targets. Quantitative proteomic analyses of EN1-bound chromatin complexes revealed association with transcriptional repressors and coactivators including TLE3, TRIM24, TRIM28, and TRIM33. High expression of
correlated with short overall survival and increased risk of developing brain metastases in patients with TNBC. Thus, EN1 is a prognostic marker and a potential therapeutic target in TNBC. SIGNIFICANCE: These findings show that the EN1 transcription factor regulates neurogenesis-related genes and is associated with brain metastasis in triple-negative breast cancer.</abstract><cop>United States</cop><pmid>31239270</pmid><doi>10.1158/0008-5472.CAN-18-3264</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-4409-012X</orcidid><orcidid>https://orcid.org/0000-0002-5835-2055</orcidid><orcidid>https://orcid.org/0000-0003-0008-4884</orcidid><orcidid>https://orcid.org/0000-0002-4037-7473</orcidid><orcidid>https://orcid.org/0000-0002-5962-9896</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Brain Neoplasms - genetics Brain Neoplasms - mortality Brain Neoplasms - secondary Co-Repressor Proteins - genetics Co-Repressor Proteins - metabolism Female Gene Expression Regulation, Neoplastic Homeodomain Proteins - genetics Humans MCF-7 Cells Prognosis Transcription Factors - genetics Triple Negative Breast Neoplasms - genetics Triple Negative Breast Neoplasms - mortality Triple Negative Breast Neoplasms - pathology Xenograft Model Antitumor Assays |
| title | EN1 Is a Transcriptional Dependency in Triple-Negative Breast Cancer Associated with Brain Metastasis |
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