ADP Ribosylation Factor Like 2 (Arl2) Regulates Breast Tumor Aggressivity in Immunodeficient Mice 英文参考文献.docVIP

ADPRibosylationFactorLike2(Arl2)RegulatesBreast TumorAggressivityinImmunodeficientMice AnneBeghin1,2.,Ste′phaneBelin3.,RoubaHageSleiman1,2,Ste′phanieBrunetManquat1,2 ,Sophie Goddard4,EricTabone4,LarsP.Jordheim1,2,IsabelleTreilleux4,Marie-FrancePoupon5 ,Jean-Jacques Diaz3,CharlesDumontet1,2* 1Inserm,U590,Lyon,France,2Universite′ Lyon1,ISPB,Lyon,France,3CNRS,CentredeGe′ne′tiqueMole′culaireetCellulaire,UMR5534,Villeurbanne,France,4Centre Le′onBe′rard,ServiceAnatomie-CytologiePathologiques,Lyon,France,5InstitutCurie,Paris,France Abstract We have previously reported that ADP ribosylation factor like 2 (Arl2), a small GTPase, content influences microtubule dynamicsandcellcycledistributioninbreasttumorcells,aswellasthedegreeanddistributionofphosphorylatedP53.Here weshow,intwodifferenthumanbreastadenocarcinomamodels,thatArl2contenthasamajorimpactonbreasttumorcell aggressivity both invitro and in vivo. Cellswith reduced contentof Arl2 displayed reducedcontact inhibition, increased clonogenicorclusterformationaswellasaproliferativeadvantageovercontrolcellsinaninvitrocompetitionassay.These cells also caused larger tumors in SCID mice, a phenotype which was mimicked by the in vivo administration of siRNA directed against Arl2. Cells with increased Arl2 content displayed reduced aggressivity, both in vitro and in vivo , with enhancednecrosisandwerealsofoundtocontainincreasedPP2Aphosphataseactivity.Art-PCRanalysisoffreshhuman tumorbreastsamplessuggestedthatlowArl2expressionwasassociatedwithlargertumorsizeandgreaterriskoflymph nodeinvolvementatdiagnosis.ThesedataunderlinetheroleofArl2,asmallGTPase,asanimportantregulatorofbreast tumorcellaggressivity,bothinvitroandinvivo. Citation:BeghinA,BelinS,HageSleimanR,BrunetManquatS,GoddardS,etal.(2009)ADPRibosylationFactorLike2(Arl2)RegulatesBreastTumorAggressivity inImmunodeficientMice.PLoSONE4(10):e7478.doi:10.1371/journal.pone.0007478 Editor:SyedA.Aziz,HealthCanada,Canada ReceivedJune17,2009;AcceptedSeptember2,2009;PublishedOctober15