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1、 ChronicCadmiumExposureStimulatesSDF-1ExpressioninanERaDependentMannerEsmeraldaPonce,NatalieB.Aquino,MaggieC.Louie*DepartmentofNaturalSciencesandMathematics,DominicanUniversityofCalifornia,SanRafael,California,UnitedStatesofAmericaAbstractCadmiumisanomnipotentenvironmentalcontaminantassociatedwithth
2、edevelopmentofbreastcancer.Studiessuggestthatcadmiumfunctionsasanendocrinedisruptor,mimickingtheactionsofestrogeninbreastcancercellsandactivatingthereceptortopromotecellgrowth.Althoughacutecadmiumexposureisknowntopromoteestrogenreceptor-mediatedgeneexpressionassociatedwithgrowth,theconsequenceofchro
3、niccadmiumexposureisunclear.Sinceheavymetalsareknown to bioaccumulate, it is necessary to understand the effects of prolonged cadmium exposure. This study aims toinvestigate the effects of chronic cadmium exposure on breast cancer progression. A MCF7 breast cancer cell linechronicallyexposedto1027MC
4、dCl2servesasourmodelsystem.Datasuggestthatprolongedcadmiumexposuresresultinthedevelopmentofmoreaggressivecancerphenotypesincreasedcellgrowth,migrationandinvasion.Theresultsfromthis study show for the first time that chronic cadmium exposure stimulates the expression of SDF-1 by altering themolecular
5、 interactions between ERa, c-jun and c-fos. This study provides a mechanistic link between chronic cadmiumexposureandERaanddemonstratesthatprolonged,low-levelcadmiumexposurecontributestobreastcancerprogression.Citation:PonceE,AquinoNB,LouieMC(2013)ChronicCadmiumExposureStimulatesSDF-1ExpressioninanE
6、RaDependentManner.PLoSONE8(8):e72639.doi:10.1371/journal.pone.0072639Editor:MasaruKatoh,NationalCancerCenter,JapanReceivedApril19,2013;AcceptedJuly11,2013;PublishedAugust28,2013Copyright: 2013 Ponce etal. This is an open-access article distributed under the terms of the Creative Commons Attribution
7、License, which permitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.Funding:ThisworkwassupportedinpartbygrantsfromtheNationalScienceFoundation(1039728toMCL)andtheNationalCancerInstitute(CA121983-02toMCLandCA121983-02S1toEP).Thefundershadnorolei
8、nstudydesign,datacollectionandanalysis,decisiontopublish,orpreparationofthemanuscript.CompetingInterests:Theauthorshavedeclaredthatnocompetinginterestsexist.*E-mail:maggie.louiedominican.eduIntroductionneoplastic growth in the mammary gland 2,4. Animal studieshavealsoshownthatcadmiumexposurecanincre
9、asethedensityofthemammaryglandsaswellasinducechangesintheliningofthe uterus, all of which are early signs of hormone-relatedtumorigenesis4,6,7.Breastcancerisoneofthemostcommonmalignanciesafflictingwomen in the United States, and it has the second highestmortalityrateassociatedwithanycancer.Themajori
10、tyofbreastcancers initially develop as hormone-dependent, with estrogenreceptorsexpressedinapproximately70%ofbreastcancercases.The presence or absence of ERa is a key determinant of theprognosis of the disease, in addition to determining whether thecancer will respond to hormone therapy or not. ERa-
11、positivebreast cancers are often hormone-responsive and are typicallytreated with antiestrogens like tamoxifen. However, hormone-dependent breast cancer frequently progresses into more malig-nant cancer phenotypes that are often hormone-independent. Inmanycases,theestrogenreceptor(ERa)isstillpresent
12、,buttheroleof ERa in hormone refractory breast tumorigenesis and itsunderlying mechanism are unclear. A potential mechanisminvolvesmetalloestrogensheavymetalsthatfunctionasendocrinedisruptorsandmimictheactionsofestrogen.Cadmium has also been shown to promote ER-dependentbreastcancercellproliferation
13、,potentiallythroughtheactivationof the ER signaling pathway 3,5,8,9. Results from our lab andothers have suggested that cells treated with cadmium expresshigher levels of ER target genes, including cyclin D1, c-myc,progesteronereceptor,andcathepsin-D3,5,8.Althoughcadmi-umisknowntobindtoERa,themechan
14、ismbehindER-mediatedgene expression and subsequent breast cancer cell growth is notcompletely established. Results from our previous study showedthat cadmium promotes the nuclear localization of ERa andenhancesthebindingofERatotargetgenepromoters8.Itwasalso demonstrated that cadmium potentiates the
15、interactionbetween ERa and c-jun, a member of the AP-1 family oftranscriptionfactors.Among the metalloestrogens, cadmium is the best character-ized. Cadmium is derived from various industrial sources,including present and former mining activities, production ofalloys,batteries,fertilizers,pigments,a
16、ndcombustionby-products.Human exposure results from the consumption of contaminatedwaterandfoodorinhalationofcigarettesmokeandcontaminatedfumes. Cadmium exposure has long been associated with thedevelopment of breast cancer 15, but the mechanism ofcadmiumsactiononbreastcancerremainselusive.Recentstudieshave suggested that ca
