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Maxwell CA, Benitez J, Gomez-Baldo L, Osorio A, Bonifaci N, Fernandez-Ramires R, Costes SV, Guino E, Chen H, Evans GJ, Mohan P, Catala I, Petit A, Aguilar H, Villanueva A, Aytes A, Serra-Musach J, Rennert G, Lejbkowicz F, Peterlongo P, Manoukian S, Peissel B, Ripamonti CB, Bonanni B, Viel A, Allavena A, Bernard L, Radice P, Friedman E, Kaufman B, Laitman Y, Dubrovsky M, Milgrom R, Jakubowska A, Cybulski C, Gorski B, Jaworska K, Durda K, Sukiennicki G, Lubinski J, Shugart YY, Domchek SM, Letrero R, Weber BL, Hogervorst FB, Rookus MA, Collee JM, Devilee P, Ligtenberg MJ, van der Luijt RB, Aalfs CM, Waisfisz Q, Wijnen J, van Roozendaal CE, Easton DF, Peock S, Cook M, Oliver C, Frost D, Harrington P, Evans DG, Lalloo F, Eeles R, Izatt L, Chu C, Eccles D, Douglas F, Brewer C, Nevanlinna H, Heikkinen T, Couch FJ, Lindor NM, Wang XS, Godwin AK, Caligo MA, Lombardi G, Loman N, Karlsson P, Ehrencrona H, von Wachenfeldt A, Barkardottir RB, Hamann U, Rashid MU, Lasa A, Caldes T, Andres R, Schmitt M, Assmann V, Stevens K, Offit K, Curado J, Tilgner H, Guigo R, Aiza G, Brunet J, Castellsague J, Martrat G, Urruticoechea A, Blanco I, Tihomirova L, Goldgar DE, Buys S, John EM, Miron A, Southey M, Daly MB, Schmutzler RK, Wappenschmidt B, Meindl A, Arnold N, Deissler H, Varon-Mateeva R, Sutter C, Niederacher D, Imyamitov E, Sinilnikova OM, Stoppa-Lyonne D, Mazoyer S, Verny-Pierre C, Castera L, de Pauw A, Bignon YJ, Uhrhammer N, Peyrat JP, Vennin P, Ferrer SF, Collonge-Rame MA, Mortemousque I, Spurdle AB, Beesley J, Chen XQ, Healey S, Barcellos-Hoff MH, Vidal M, Gruber SB, Lazaro C, Capella G, McGuffog L, Nathanson KL, Antoniou AC, Chenevix-Trench G, Fleisch MC, Moreno V, Pujana MA
Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer
Plos Biology (2011) 9:e1001199.
Abstract
Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
Note
Publication Date: 2011-11-01.
PMCID: PMC3217025
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