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1、Page1of46AcceptedPreprintfirstpostedon23May2014asManuscriptERC-13-04701BiologicandClinicalSignificanceofAndrogenReceptorVariantsinCastrationResistant2ProstateCancer345678KathrynEWare(1),MarianoAGarcia-Blanco(1,2),AndrewJArmstrong(1,2),9andScottM.Dehm*(3,4)1011*correspondingauthor:12
2、ScottDehmPhD,MasonicCancerCenter,UniversityofMinnesota,MayoMailCode806,42013DelawareSt.SE,Minneapolis,MN55455dehm@umn.edu1415161)DukeUniversity,213ResearchDr.,0045CARLBldg.,DepartmentsofMolecular17GeneticsandMedicine,andMedicine,DurhamNC27710USA182)DukeCancerInstitute,DepartmentofMe
3、dicine,DukeUniversity,DurhamNCUSA193)MasonicCancerCenter,UniversityofMinnesotaMasonicCancerCenter,Minneapolis,20MNUSA21DepartmentofLaboratoryMedicineandPathology,UniversityofMinnesota,22Minneapolis,MNUSA23ShortTitle:TheRoleofARVariantsinCRPC24Keywords:Androgenreceptor,splicevariants
4、,castrationresistantprostatecancer,AR25variants,metastasis,epithelialtomesenchymaltransition26WordCount:7172words1Copyright©2014bytheSocietyforEndocrinology.Page2of4627Abstract2829Asprostatecancerprogressestothelethalcastrationresistantandmetastaticform,geneticand30epigeneticadaptat
5、ion,clonalselection,andevolutionofthetumormicroenvironmentcontribute31totheemergenceofuniquebiologiccharacteristicsundertheselectivepressureofexternal32stresses.Thesestressesincludethetherapiesappliedintheclinicorlaboratoryandthe33exposuresofcancerstohormonal,paracrine,orautocrinest
6、imuliinthecontextofthetumor34micro-andmacro-environment.Theandrogenreceptor(AR)isakeygeneinvolvedinprostate35canceretiologyandoncogenesis,includingdiseasedevelopment,progression,responseto36initialhormonaltherapies,andsubsequentresistancetohormonaltherapies.Alterationsinthe37ARsigna
7、lingpathwayhavebeenobservedincertainselectioncontextsandcontributetothe38resistancetoagentsthattargethormonalregulationoftheAR,includingstandardandrogen39deprivationtherapy(ADT),anti-androgenssuchasenzalutamide,andandrogensynthesis40inhibitionwithabirateroneacetate.Onesuchresistance
8、mechanismisthesynth
