Transcriptional Network Analysis Identifies BACH1 as a Master Regulator of Breast Cancer Bone Metastasis
The application of functional genomic analysis of breast cancer metastasis has led to the identification of a growing number of organ-specific metastasis genes, which often function in concert to facilitate different steps of the metastatic cascade. However, the gene regulatory network that controls...
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| Veröffentlicht in: | The Journal of biological chemistry 2012-09, Vol.287 (40), p.33533-33544 |
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| container_title | The Journal of biological chemistry |
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| creator | Liang, Yajun Wu, Heng Lei, Rong Chong, Robert A. Wei, Yong Lu, Xin Tagkopoulos, Ilias Kung, Sun-Yuan Yang, Qifeng Hu, Guohong Kang, Yibin |
| description | The application of functional genomic analysis of breast cancer metastasis has led to the identification of a growing number of organ-specific metastasis genes, which often function in concert to facilitate different steps of the metastatic cascade. However, the gene regulatory network that controls the expression of these metastasis genes remains largely unknown. Here, we demonstrate a computational approach for the deconvolution of transcriptional networks to discover master regulators of breast cancer bone metastasis. Several known regulators of breast cancer bone metastasis such as Smad4 and HIF1 were identified in our analysis. Experimental validation of the networks revealed BACH1, a basic leucine zipper transcription factor, as the common regulator of several functional metastasis genes, including MMP1 and CXCR4. Ectopic expression of BACH1 enhanced the malignance of breast cancer cells, and conversely, BACH1 knockdown significantly reduced bone metastasis. The expression of BACH1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. This study established BACH1 as the master regulator of breast cancer bone metastasis and provided a paradigm to identify molecular determinants in complex pathological processes.
Background: The transcriptional network governing cancer metastasis is largely unexplored.
Results: BACH1 regulates multiple metastasis genes and promotes breast cancer metastasis to bone.
Conclusion: BACH1 is a master regulator of breast cancer bone metastasis and transcriptional network reverse engineering is helpful to identify novel functional genes of metastasis.
Significance: This study provides a systems biology approach to identify master regulators of complicated biological processes. |
| doi_str_mv | 10.1074/jbc.M112.392332 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3460454</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0021925820628563</els_id><sourcerecordid>1081872487</sourcerecordid><originalsourceid>FETCH-LOGICAL-c555t-c4b3a83731a2764e67d1b09ca47a8fae53e457261bc913621e115753adefeb7e3</originalsourceid><addsrcrecordid>eNp1kc1PGzEQxa2qqKS0594qH3vZ4M_17qVSEtGCREBCVOrNmvXOgulmndoOFf99jUIRHOqL5Znn34zeI-QTZ3POjDq-69x8zbmYy1ZIKd6QGWeNrKTmP9-SGWOCV63QzSF5n9IdK0e1_B05FKIxutFyRm6vI0zJRb_NPkww0gvMf0L8RRfl8ZB8omc9TtkPHhNdLlannEKiQNeQMkZ6hTe7EXKINAx0GbFU6QomV1rLMCFdYy4lKJwP5GCAMeHHp_uI_Ph2cr06rc4vv5-tFueV01rnyqlOQiON5CBMrbA2Pe9Y60AZaAZALVFpI2reuZbLWnDkXBstoccBO4PyiHzdc7e7boO9K8tHGO02-g3EBxvA29edyd_am3BvpaqZ0qoAvjwBYvi9w5TtxieH4wgThl2yxWDeGKEaU6THe6mLIaWIw_MYzuxjPrbkYx_zsft8yo_PL7d71v8LpAjavQCLR_ceo03OYzG09xFdtn3w_4X_BT2VoHM</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1081872487</pqid></control><display><type>article</type><title>Transcriptional Network Analysis Identifies BACH1 as a Master Regulator of Breast Cancer Bone Metastasis</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Liang, Yajun ; Wu, Heng ; Lei, Rong ; Chong, Robert A. ; Wei, Yong ; Lu, Xin ; Tagkopoulos, Ilias ; Kung, Sun-Yuan ; Yang, Qifeng ; Hu, Guohong ; Kang, Yibin</creator><creatorcontrib>Liang, Yajun ; Wu, Heng ; Lei, Rong ; Chong, Robert A. ; Wei, Yong ; Lu, Xin ; Tagkopoulos, Ilias ; Kung, Sun-Yuan ; Yang, Qifeng ; Hu, Guohong ; Kang, Yibin</creatorcontrib><description>The application of functional genomic analysis of breast cancer metastasis has led to the identification of a growing number of organ-specific metastasis genes, which often function in concert to facilitate different steps of the metastatic cascade. However, the gene regulatory network that controls the expression of these metastasis genes remains largely unknown. Here, we demonstrate a computational approach for the deconvolution of transcriptional networks to discover master regulators of breast cancer bone metastasis. Several known regulators of breast cancer bone metastasis such as Smad4 and HIF1 were identified in our analysis. Experimental validation of the networks revealed BACH1, a basic leucine zipper transcription factor, as the common regulator of several functional metastasis genes, including MMP1 and CXCR4. Ectopic expression of BACH1 enhanced the malignance of breast cancer cells, and conversely, BACH1 knockdown significantly reduced bone metastasis. The expression of BACH1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. This study established BACH1 as the master regulator of breast cancer bone metastasis and provided a paradigm to identify molecular determinants in complex pathological processes.
Background: The transcriptional network governing cancer metastasis is largely unexplored.
Results: BACH1 regulates multiple metastasis genes and promotes breast cancer metastasis to bone.
Conclusion: BACH1 is a master regulator of breast cancer bone metastasis and transcriptional network reverse engineering is helpful to identify novel functional genes of metastasis.
Significance: This study provides a systems biology approach to identify master regulators of complicated biological processes.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M112.392332</identifier><identifier>PMID: 22875853</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Basic-Leucine Zipper Transcription Factors - genetics ; Basic-Leucine Zipper Transcription Factors - physiology ; Bone ; Bone and Bones - pathology ; Bone Neoplasms - secondary ; Breast Cancer ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cancer ; Cell Line, Tumor ; Fanconi Anemia Complementation Group Proteins - genetics ; Fanconi Anemia Complementation Group Proteins - physiology ; Female ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Humans ; Hypoxia ; Mammary Neoplasms, Animal - metabolism ; Matrix Metalloproteinase 1 - metabolism ; Metastasis ; Mice ; Mice, Nude ; Molecular Bases of Disease ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Neoplasms - pathology ; Promoter Regions, Genetic ; Smad Proteins - metabolism ; SMAD Transcription Factor ; Transcription Factors ; Transcription, Genetic</subject><ispartof>The Journal of biological chemistry, 2012-09, Vol.287 (40), p.33533-33544</ispartof><rights>2012 © 2012 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2012 by The American Society for Biochemistry and Molecular Biology, Inc. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c555t-c4b3a83731a2764e67d1b09ca47a8fae53e457261bc913621e115753adefeb7e3</citedby><cites>FETCH-LOGICAL-c555t-c4b3a83731a2764e67d1b09ca47a8fae53e457261bc913621e115753adefeb7e3</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/PMC3460454/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460454/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22875853$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liang, Yajun</creatorcontrib><creatorcontrib>Wu, Heng</creatorcontrib><creatorcontrib>Lei, Rong</creatorcontrib><creatorcontrib>Chong, Robert A.</creatorcontrib><creatorcontrib>Wei, Yong</creatorcontrib><creatorcontrib>Lu, Xin</creatorcontrib><creatorcontrib>Tagkopoulos, Ilias</creatorcontrib><creatorcontrib>Kung, Sun-Yuan</creatorcontrib><creatorcontrib>Yang, Qifeng</creatorcontrib><creatorcontrib>Hu, Guohong</creatorcontrib><creatorcontrib>Kang, Yibin</creatorcontrib><title>Transcriptional Network Analysis Identifies BACH1 as a Master Regulator of Breast Cancer Bone Metastasis</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The application of functional genomic analysis of breast cancer metastasis has led to the identification of a growing number of organ-specific metastasis genes, which often function in concert to facilitate different steps of the metastatic cascade. However, the gene regulatory network that controls the expression of these metastasis genes remains largely unknown. Here, we demonstrate a computational approach for the deconvolution of transcriptional networks to discover master regulators of breast cancer bone metastasis. Several known regulators of breast cancer bone metastasis such as Smad4 and HIF1 were identified in our analysis. Experimental validation of the networks revealed BACH1, a basic leucine zipper transcription factor, as the common regulator of several functional metastasis genes, including MMP1 and CXCR4. Ectopic expression of BACH1 enhanced the malignance of breast cancer cells, and conversely, BACH1 knockdown significantly reduced bone metastasis. The expression of BACH1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. This study established BACH1 as the master regulator of breast cancer bone metastasis and provided a paradigm to identify molecular determinants in complex pathological processes.
Background: The transcriptional network governing cancer metastasis is largely unexplored.
Results: BACH1 regulates multiple metastasis genes and promotes breast cancer metastasis to bone.
Conclusion: BACH1 is a master regulator of breast cancer bone metastasis and transcriptional network reverse engineering is helpful to identify novel functional genes of metastasis.
Significance: This study provides a systems biology approach to identify master regulators of complicated biological processes.</description><subject>Animals</subject><subject>Basic-Leucine Zipper Transcription Factors - genetics</subject><subject>Basic-Leucine Zipper Transcription Factors - physiology</subject><subject>Bone</subject><subject>Bone and Bones - pathology</subject><subject>Bone Neoplasms - secondary</subject><subject>Breast Cancer</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Fanconi Anemia Complementation Group Proteins - genetics</subject><subject>Fanconi Anemia Complementation Group Proteins - physiology</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Regulatory Networks</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Mammary Neoplasms, Animal - metabolism</subject><subject>Matrix Metalloproteinase 1 - metabolism</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Molecular Bases of Disease</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplasm Metastasis</subject><subject>Neoplasms - pathology</subject><subject>Promoter Regions, Genetic</subject><subject>Smad Proteins - metabolism</subject><subject>SMAD Transcription Factor</subject><subject>Transcription Factors</subject><subject>Transcription, Genetic</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1PGzEQxa2qqKS0594qH3vZ4M_17qVSEtGCREBCVOrNmvXOgulmndoOFf99jUIRHOqL5Znn34zeI-QTZ3POjDq-69x8zbmYy1ZIKd6QGWeNrKTmP9-SGWOCV63QzSF5n9IdK0e1_B05FKIxutFyRm6vI0zJRb_NPkww0gvMf0L8RRfl8ZB8omc9TtkPHhNdLlannEKiQNeQMkZ6hTe7EXKINAx0GbFU6QomV1rLMCFdYy4lKJwP5GCAMeHHp_uI_Ph2cr06rc4vv5-tFueV01rnyqlOQiON5CBMrbA2Pe9Y60AZaAZALVFpI2reuZbLWnDkXBstoccBO4PyiHzdc7e7boO9K8tHGO02-g3EBxvA29edyd_am3BvpaqZ0qoAvjwBYvi9w5TtxieH4wgThl2yxWDeGKEaU6THe6mLIaWIw_MYzuxjPrbkYx_zsft8yo_PL7d71v8LpAjavQCLR_ceo03OYzG09xFdtn3w_4X_BT2VoHM</recordid><startdate>20120928</startdate><enddate>20120928</enddate><creator>Liang, Yajun</creator><creator>Wu, Heng</creator><creator>Lei, Rong</creator><creator>Chong, Robert A.</creator><creator>Wei, Yong</creator><creator>Lu, Xin</creator><creator>Tagkopoulos, Ilias</creator><creator>Kung, Sun-Yuan</creator><creator>Yang, Qifeng</creator><creator>Hu, Guohong</creator><creator>Kang, Yibin</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><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></search><sort><creationdate>20120928</creationdate><title>Transcriptional Network Analysis Identifies BACH1 as a Master Regulator of Breast Cancer Bone Metastasis</title><author>Liang, Yajun ; Wu, Heng ; Lei, Rong ; Chong, Robert A. ; Wei, Yong ; Lu, Xin ; Tagkopoulos, Ilias ; Kung, Sun-Yuan ; Yang, Qifeng ; Hu, Guohong ; Kang, Yibin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c555t-c4b3a83731a2764e67d1b09ca47a8fae53e457261bc913621e115753adefeb7e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Basic-Leucine Zipper Transcription Factors - genetics</topic><topic>Basic-Leucine Zipper Transcription Factors - physiology</topic><topic>Bone</topic><topic>Bone and Bones - pathology</topic><topic>Bone Neoplasms - secondary</topic><topic>Breast Cancer</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Fanconi Anemia Complementation Group Proteins - genetics</topic><topic>Fanconi Anemia Complementation Group Proteins - physiology</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Regulatory Networks</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Mammary Neoplasms, Animal - metabolism</topic><topic>Matrix Metalloproteinase 1 - metabolism</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Molecular Bases of Disease</topic><topic>Neoplasm Invasiveness</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasms - pathology</topic><topic>Promoter Regions, Genetic</topic><topic>Smad Proteins - metabolism</topic><topic>SMAD Transcription Factor</topic><topic>Transcription Factors</topic><topic>Transcription, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liang, Yajun</creatorcontrib><creatorcontrib>Wu, Heng</creatorcontrib><creatorcontrib>Lei, Rong</creatorcontrib><creatorcontrib>Chong, Robert A.</creatorcontrib><creatorcontrib>Wei, Yong</creatorcontrib><creatorcontrib>Lu, Xin</creatorcontrib><creatorcontrib>Tagkopoulos, Ilias</creatorcontrib><creatorcontrib>Kung, Sun-Yuan</creatorcontrib><creatorcontrib>Yang, Qifeng</creatorcontrib><creatorcontrib>Hu, Guohong</creatorcontrib><creatorcontrib>Kang, Yibin</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liang, Yajun</au><au>Wu, Heng</au><au>Lei, Rong</au><au>Chong, Robert A.</au><au>Wei, Yong</au><au>Lu, Xin</au><au>Tagkopoulos, Ilias</au><au>Kung, Sun-Yuan</au><au>Yang, Qifeng</au><au>Hu, Guohong</au><au>Kang, Yibin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transcriptional Network Analysis Identifies BACH1 as a Master Regulator of Breast Cancer Bone Metastasis</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2012-09-28</date><risdate>2012</risdate><volume>287</volume><issue>40</issue><spage>33533</spage><epage>33544</epage><pages>33533-33544</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The application of functional genomic analysis of breast cancer metastasis has led to the identification of a growing number of organ-specific metastasis genes, which often function in concert to facilitate different steps of the metastatic cascade. However, the gene regulatory network that controls the expression of these metastasis genes remains largely unknown. Here, we demonstrate a computational approach for the deconvolution of transcriptional networks to discover master regulators of breast cancer bone metastasis. Several known regulators of breast cancer bone metastasis such as Smad4 and HIF1 were identified in our analysis. Experimental validation of the networks revealed BACH1, a basic leucine zipper transcription factor, as the common regulator of several functional metastasis genes, including MMP1 and CXCR4. Ectopic expression of BACH1 enhanced the malignance of breast cancer cells, and conversely, BACH1 knockdown significantly reduced bone metastasis. The expression of BACH1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. This study established BACH1 as the master regulator of breast cancer bone metastasis and provided a paradigm to identify molecular determinants in complex pathological processes.
Background: The transcriptional network governing cancer metastasis is largely unexplored.
Results: BACH1 regulates multiple metastasis genes and promotes breast cancer metastasis to bone.
Conclusion: BACH1 is a master regulator of breast cancer bone metastasis and transcriptional network reverse engineering is helpful to identify novel functional genes of metastasis.
Significance: This study provides a systems biology approach to identify master regulators of complicated biological processes.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22875853</pmid><doi>10.1074/jbc.M112.392332</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Basic-Leucine Zipper Transcription Factors - genetics Basic-Leucine Zipper Transcription Factors - physiology Bone Bone and Bones - pathology Bone Neoplasms - secondary Breast Cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer Cell Line, Tumor Fanconi Anemia Complementation Group Proteins - genetics Fanconi Anemia Complementation Group Proteins - physiology Female Gene Expression Regulation, Neoplastic Gene Regulatory Networks Humans Hypoxia Mammary Neoplasms, Animal - metabolism Matrix Metalloproteinase 1 - metabolism Metastasis Mice Mice, Nude Molecular Bases of Disease Neoplasm Invasiveness Neoplasm Metastasis Neoplasms - pathology Promoter Regions, Genetic Smad Proteins - metabolism SMAD Transcription Factor Transcription Factors Transcription, Genetic |
| title | Transcriptional Network Analysis Identifies BACH1 as a Master Regulator of Breast Cancer Bone Metastasis |
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