Genetic Differences in Transcript Responses to Low-Dose Ionizing Radiation Identify Tissue Functions Associated with Breast Cancer Susceptibility 英文参考文献.docVIP

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Genetic Differences in Transcript Responses to Low-Dose Ionizing Radiation Identify Tissue Functions Associated with Breast Cancer Susceptibility 英文参考文献.doc

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Genetic Differences in Transcript Responses to Low-Dose Ionizing Radiation Identify Tissue Functions Associated with Breast Cancer Susceptibility 英文参考文献

GeneticDifferencesinTranscriptResponsestoLow-Dose IonizingRadiationIdentifyTissueFunctionsAssociated withBreastCancerSusceptibility AntoineM.Snijders,FrancescoMarchetti¤a,SandhyaBhatnagar,NadireDuru,JuHan,ZhiHu¤b, Jian-HuaMao,JoeW.Gray¤b,AndrewJ.Wyrobek* LifeSciencesDivision,LawrenceBerkeleyNationalLaboratory,Berkeley,California,UnitedStatesofAmerica Abstract High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, ,10cGy)exposures remain highlyuncertain.We explored asystems approach thatcompared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. UnirradiatedmammaryandbloodtissuesofthesestrainsdifferedsignificantlyinbaselineexpressionsofDNArepair,tumor suppressor,andstressresponsegenes.LDexposuresof7.5cGy(weeklyfor4weeks)didnotinducedetectablegenomic instabilityineitherstrain.However,themammaryglandsofthesensitivestrainbutnottheresistantstrainshowedearly transcriptionalresponsesinvolving:(a)diminishedimmuneresponse,(b)increasedcellularstress,(c)alteredTGFb-signaling, and(d)inappropriateexpressionofdevelopmentalgenes.OnemonthafterLDexposure,thetwostrainsshowedopposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p=0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p,0.0001).ThereisconcordantdirectionofexpressionintheLD-exposedsensitivemousestrain,inbiomarkersofhuman DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice ar