Allelic Variation and Differential Expression of the mSIN3A Histone Deacetylase Complex Gene Arid4b Promote Mammary Tumor Growth and Metastasis 英文参考文献.docVIP

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Allelic Variation and Differential Expression of the mSIN3A Histone Deacetylase Complex Gene Arid4b Promote Mammary Tumor Growth and Metastasis 英文参考文献.doc

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Allelic Variation and Differential Expression of the mSIN3A Histone Deacetylase Complex Gene Arid4b Promote Mammary Tumor Growth and Metastasis 英文参考文献

AllelicVariationandDifferentialExpressionofthe mSIN3AHistoneDeacetylaseComplexGeneArid4b PromoteMammaryTumorGrowthandMetastasis ScottF.Winter1,LuanneLukes1,RenardC.Walker1,DannyR.Welch2,KentW.Hunter1* 1Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America, 2Department of CancerBiology,UniversityofKansasMedicalCenter,KansasCity,Kansas,UnitedStatesofAmerica Abstract Accumulating evidence suggests that breast cancer metastatic progression is modified by germline polymorphism, although specific modifier genes have remained largely undefined. In the current study, we employ the MMTV-PyMT transgenicmousemodelandtheAKXDpanelofrecombinantinbredmicetoidentifyAT–richinteractivedomain4B(Arid4b; NM_194262)asabreastcancerprogressionmodifiergene.EctopicexpressionofArid4bpromotedprimarytumorgrowthin vivoaswellasincreasedmigrationandinvasioninvitro,andthephenotypewasassociatedwithpolymorphismsidentified betweentheAKR/JandDBA/2Jallelesaspredictedbyourgeneticanalyses.StableshRNA–mediatedknockdownofArid4b causedasignificantreductioninpulmonarymetastases,validatingaroleforArid4basametastasismodifiergene.ARID4B physicallyinteractswiththebreastcancermetastasissuppressorBRMS1,andwedetecteddifferentialbindingoftheArid4b allelestohistonedeacetylasecomplexmembersmSIN3AandmSDS3,suggestingthatthemechanismofArid4bactionlikely involvesinteractionswithchromatinmodifyingcomplexes.DownregulationoftheconservedTpx2genenetwork,whichis comprised of many factors regulating cell cycle and mitotic spindle biology, was observed concomitant with loss of metastaticefficiencyinArid4bknockdowncells.Consistentwithourgeneticanalysisandinvivoexperimentsinourmouse model system, ARID4B expression was also an independent predictor of distant metastasis-free survival in breast cancer patientswithER+tumors.ThesestudiessupportacausativeroleofARID4Binmetastaticprogressionofbreastcancer. Citation:WinterSF,LukesL,WalkerRC,WelchDR