Poly(ADP-ribose) polymerase-1 plays a role in suppressing mammary tumourigenesis in mice

The DNA strand break-binding molecule, poly(ADP-ribose) polymerase-1 (PARP-1), plays a role in DNArepair, chromosomal stability, transcription and celldeath. Accumulating evidence suggests that dysfunctionofPARP-1contributestotumorigenesis.Here,wereportthat PARP-1 deficiency causes mammary carcinomaformation in female mice, and that the introduction ofTrp53 mutations accelerates the onset and shortens thelatencyofmammarytumorigenesis.WeshowthatPARP-1 deficiency results in chromosomal aneuploidy andcentrosome amplification, which are substantiated by theinactivation of Trp53 in primary mammary epithelial(PME) cells. In addition, PARP-1 deficiency compro-mises p53 activation and impairs BRCA1 recruitment tothe sites of DNA damage in PME cells. PARP-1complementation partly rescues the defective DNAdamage response mediated by p53 and BRCA1. Thepresent study thus identifies a role of PARP-1 insuppressing mammary tumorigenesis in vivo and suggeststhat dysfunction of PARP-1 may be a risk factor forbreast cancer in humans.Oncogene(2007)26,3857–3867.doi:10.1038/sj.onc.1210156;publishedonline11December2006Keywords: breastcancer;DNAdamageresponse;PARP-1;p53;BRCA1IntroductionPoly(ADP-ribose)polymerase-1(PARP-1),amemberofthePARPsuperfamily,isaDNAstrandbreak-sensingprotein,anditsactivationisoneoftheearlyresponsestoDNA damage (Ame etal.,2004). PARP-1catalysespoly ADP-ribosylation, an immediate DNA-damage-dependent post-translational modification of histonesand other nuclear proteins, and may play a multi-functional role in various cellular processes, includingDNA damage detection and repair, chromatinmodification, transcription, cell death pathways,insulator function and mitotic apparatus function.These processes indicate a critical role of PARP-1 formany physiological and pathophysiological outcomes,including genome maintenance, carcinogenesis, aging,inflammation and neuronal function (reviewed in Kimetal.,2005).Genomic instability is a hallmark of tumorigenesis(Hanahan and Weinberg, 2000). Recent studies usingPARP-1mutant mice have implicated PARP-1 in thesuppression of tumorigenesis (Tong et al., 2001a;Masutani et al., 2003). Although PARP-1 / micedevelop spontaneous tumors at a low incidence (Tongetal.,2002),theyaresusceptibletochemicalcarcinogen-induced tumorigenesis, with increased mutation rates(Tsutsumietal.,2001;Nozakietal.,2003;Shibataetal.,2005).InactivationofPARP-1hasbeenshowntoresultin a high frequency of T-cell lymphomas in severecombined immunodeficiency mice (Morrison et al.,1997). In addition, PARP-1 deficiency provoked theformationofvariousepithelialandneuronaltumor,andshortened the latency of lymphoma in Trp53mutantmice (Beneke and Moroy, 2001; Tong etal., 2001b,2003).Moreover,haploinsufficiencyofnon-homologousend-joining molecule Ku80promoted hepatocellularcarcinomas in PARP-1-deficient mice (Tong et al.,2002),andPARP-1cooperatedwithWernersyndromeprotein in the maintenance of chromosomal integrityandinsuppressingtumorigenesis(Lebeletal.,2003).Breastcancerisoneofthemost common malignan-cies, with more than one million cases occurringworldwide annually, and is the second-leading causeof cancer mortality affecting women (Stewart andKleihues,2003).Mutationsinthebreastcancersuscep-tibilitygenesBRCA1andBRCA2,whichareinvolvedinDNA double strand break (DSB) repair and homo-logous recombination, are associated with high-penetrancehumanhereditarybreastcancer,andaccountfor5–9%ofallbreastcancers(Venkitaraman,2002).Inaddition,mutationsintumorsuppressorgeneTrp53are