Meta-Analysis and Gene Set Enrichment Relative to ER Status Reveal Elevated Activity of MYC and E2F in the “Basal” Breast Cancer Subgroup 英文参考文献.docVIP

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Meta-Analysis and Gene Set Enrichment Relative to ER Status Reveal Elevated Activity of MYC and E2F in the “Basal” Breast Cancer Subgroup 英文参考文献.doc

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Meta-Analysis and Gene Set Enrichment Relative to ER Status Reveal Elevated Activity of MYC and E2F in the “Basal” Breast Cancer Subgroup 英文参考文献

Meta-AnalysisandGeneSetEnrichmentRelativetoER StatusRevealElevatedActivityofMYCandE2Finthe ‘‘Basal’’BreastCancerSubgroup M.ChehaniAlles1.,MargaretGardiner-Garden1.,DavidJ.Nott2,YixinWang3,JohnA.Foekens4, RobertL.Sutherland1,ElizabethA.Musgrove1,ChristopherJ.Ormandy1* 1CancerResearchProgram,GarvanInstituteofMedicalResearch,Sydney,Australia,2DepartmentofStatisticsandAppliedProbability,NationalUniversityofSingapore, Singapore, Singapore, 3Veridex LLC, a Johnson Johnson Company, North Raritan, New Jersey, United States of America, 4Erasmus MC Rotterdam, Department of MedicalOncology,JosephineNefkensInstituteandCancerGenomicsCentre,Rotterdam,theNetherlands Abstract Background:Breastcancerslackingtheestrogenreceptor(ER)canbedistinguishedfromotherbreastcancersonthebasis of poor prognosis, high grade, distinctive histopathology and unique molecular signatures. These features further distinguish estrogen receptor negative (ER2) tumor subtypes, but targeted therapy is currently limited to tumors over- expressingtheErbB2receptor. Methodology/Principal Findings: To uncover the pathways against which future therapies could be developed we undertook a meta-analysis of gene expression from five large microarray datasets relative to ER status. A measure of associationwithERstatuswascalculatedforeveryAffymetrixHG-U133Aprobesetandthepathwaysthatdistinguished ER2tumorsweredefinedbytestingforenrichmentofbiologicallydefinedgenesetsusingGeneSetEnrichmentAnalysis (GSEA). As expected, the expression of the direct transcriptional targets of the ER was muted in ER2 tumors, but the expressionofgenesindirectlyregulatedbyestrogenwasenhanced.WealsoobservedenrichmentofindependentMYC- and E2F-driven transcriptional programs. We used a cell model of estrogen and MYC action to define the interaction betweenestrogenandMYCtranscriptionalactivityinbreastcancer.WefoundthatthebasalsubgroupofER2breastcancer showedastrongMYCtranscriptionalresponsethatreproducedtheindirectestrogenresponseseeninestrogenre