Insulin Receptor Substrate Adaptor Proteins Mediate Prognostic Gene Expression Profiles in Breast Cancer
Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstrea...
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| description | Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. In addition, the prognostic value of IRS proteins was significant in the luminal B breast tumor subtype. Univariate and multivariate analyses confirmed that IRS adaptor signatures correlated with poor outcome as measured by recurrence-free and overall survival. Thus, IRS adaptor protein expression is required for IGF ligand responses in breast cancer cells. IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer. |
| doi_str_mv | 10.1371/journal.pone.0150564 |
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We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. In addition, the prognostic value of IRS proteins was significant in the luminal B breast tumor subtype. Univariate and multivariate analyses confirmed that IRS adaptor signatures correlated with poor outcome as measured by recurrence-free and overall survival. Thus, IRS adaptor protein expression is required for IGF ligand responses in breast cancer cells. IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0150564</identifier><identifier>PMID: 26991655</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adaptor proteins ; Analysis ; Apoptosis ; Biology and Life Sciences ; Biomarkers ; Breast cancer ; Breast Neoplasms - diagnosis ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cancer ; Cell culture ; Cell growth ; Cell Line, Tumor ; Cell migration ; Correlation analysis ; Development and progression ; Female ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genetic aspects ; Humans ; Insulin ; Insulin receptor substrate 1 ; Insulin Receptor Substrate Proteins - biosynthesis ; Insulin-like growth factor I ; Insulin-like growth factors ; Isoforms ; Kinases ; Ligands ; Medical prognosis ; Medicine and Health Sciences ; Metastasis ; Neoplasm Proteins - biosynthesis ; Neuroblastoma ; Phenotypes ; Phosphorylation ; Physiological aspects ; Prognosis ; Proteins ; Receptor mechanisms ; Signaling ; Signatures ; Substrates ; Transforming Growth Factor beta2 - biosynthesis ; Tumors</subject><ispartof>PloS one, 2016-03, Vol.11 (3), p.e0150564-e0150564</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Becker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Becker et al 2016 Becker et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-38b724aa8023bd201ff62fe42b25820d2b3e34168bd3f19e860a0a983b7cec9a3</citedby><cites>FETCH-LOGICAL-c692t-38b724aa8023bd201ff62fe42b25820d2b3e34168bd3f19e860a0a983b7cec9a3</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/PMC4798554/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798554/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26991655$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Becker, Marc A</creatorcontrib><creatorcontrib>Ibrahim, Yasir H</creatorcontrib><creatorcontrib>Oh, Annabell S</creatorcontrib><creatorcontrib>Fagan, Dedra H</creatorcontrib><creatorcontrib>Byron, Sara A</creatorcontrib><creatorcontrib>Sarver, Aaron L</creatorcontrib><creatorcontrib>Lee, Adrian V</creatorcontrib><creatorcontrib>Shaw, Leslie M</creatorcontrib><creatorcontrib>Fan, Cheng</creatorcontrib><creatorcontrib>Perou, Charles M</creatorcontrib><creatorcontrib>Yee, Douglas</creatorcontrib><title>Insulin Receptor Substrate Adaptor Proteins Mediate Prognostic Gene Expression Profiles in Breast Cancer</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. 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IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer.</description><subject>Adaptor proteins</subject><subject>Analysis</subject><subject>Apoptosis</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - diagnosis</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer</subject><subject>Cell culture</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Correlation analysis</subject><subject>Development and progression</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetic aspects</subject><subject>Humans</subject><subject>Insulin</subject><subject>Insulin receptor substrate 1</subject><subject>Insulin Receptor Substrate Proteins - 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diagnosis</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cancer</topic><topic>Cell culture</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Correlation analysis</topic><topic>Development and progression</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genetic aspects</topic><topic>Humans</topic><topic>Insulin</topic><topic>Insulin receptor substrate 1</topic><topic>Insulin Receptor Substrate Proteins - biosynthesis</topic><topic>Insulin-like growth factor I</topic><topic>Insulin-like growth factors</topic><topic>Isoforms</topic><topic>Kinases</topic><topic>Ligands</topic><topic>Medical prognosis</topic><topic>Medicine and Health Sciences</topic><topic>Metastasis</topic><topic>Neoplasm Proteins - biosynthesis</topic><topic>Neuroblastoma</topic><topic>Phenotypes</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Prognosis</topic><topic>Proteins</topic><topic>Receptor mechanisms</topic><topic>Signaling</topic><topic>Signatures</topic><topic>Substrates</topic><topic>Transforming Growth Factor beta2 - 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We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. In addition, the prognostic value of IRS proteins was significant in the luminal B breast tumor subtype. Univariate and multivariate analyses confirmed that IRS adaptor signatures correlated with poor outcome as measured by recurrence-free and overall survival. Thus, IRS adaptor protein expression is required for IGF ligand responses in breast cancer cells. IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26991655</pmid><doi>10.1371/journal.pone.0150564</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor proteins Analysis Apoptosis Biology and Life Sciences Biomarkers Breast cancer Breast Neoplasms - diagnosis Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer Cell culture Cell growth Cell Line, Tumor Cell migration Correlation analysis Development and progression Female Gene expression Gene Expression Regulation, Neoplastic Genetic aspects Humans Insulin Insulin receptor substrate 1 Insulin Receptor Substrate Proteins - biosynthesis Insulin-like growth factor I Insulin-like growth factors Isoforms Kinases Ligands Medical prognosis Medicine and Health Sciences Metastasis Neoplasm Proteins - biosynthesis Neuroblastoma Phenotypes Phosphorylation Physiological aspects Prognosis Proteins Receptor mechanisms Signaling Signatures Substrates Transforming Growth Factor beta2 - biosynthesis Tumors |
| title | Insulin Receptor Substrate Adaptor Proteins Mediate Prognostic Gene Expression Profiles in Breast Cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T17%3A18%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Insulin%20Receptor%20Substrate%20Adaptor%20Proteins%20Mediate%20Prognostic%20Gene%20Expression%20Profiles%20in%20Breast%20Cancer&rft.jtitle=PloS%20one&rft.au=Becker,%20Marc%20A&rft.date=2016-03-18&rft.volume=11&rft.issue=3&rft.spage=e0150564&rft.epage=e0150564&rft.pages=e0150564-e0150564&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0150564&rft_dat=%3Cgale_plos_%3EA453470885%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1774316973&rft_id=info:pmid/26991655&rft_galeid=A453470885&rft_doaj_id=oai_doaj_org_article_b3a2a113adc349f9a86de76741740fe5&rfr_iscdi=true |