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Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer

Lookup NU author(s): Dr Fiona Douglas

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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 (wHR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, wHR = 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.


Publication metadata

Author(s): Maxwell CA, Benitez J, Gomez-Baldo L, Osorio A, Bonifaci N, Fernandez-Ramires R, Costes SV, Guino E, Chen H, Evans GJR, 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 FBL, Rookus MA, Collee JM, Devilee P, Ligtenberg MJ, van der Luijt RB, Aalfs CM, Waisfisz Q, Wijnen J, van Roozendaal CEP, 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, HEBON, EMBRACE, SWE-BRCA, BCFR, GEMO Study Collaborators, kConFab

Publication type: Article

Publication status: Published

Journal: PLoS Biology

Year: 2011

Volume: 9

Issue: 11

Print publication date: 15/11/2011

Date deposited: 27/02/2012

ISSN (electronic): 1544-9173

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pbio.1001199

DOI: 10.1371/journal.pbio.1001199


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Funding

Funder referenceFunder name
"Ramon y Cajal" Young Investigator Program
Cancer Foundation of Western Australia
Fondazione Cassa di Risparmio di Pisa (Istituto Toscano Tumori)
Fondazione Italiana per la Ricerca sul Cancro ("Hereditary Tumors")
Komen Foundation
Ligue National Contre le Cancer (France)
National Breast Cancer Foundation (Australia)
Queensland Cancer Fund
Ramon Areces Foundation
Sigrid Juselius Foundation
Spanish Biomedical Research Centre Networks for Epidemiology and Public Health, and Rare Diseases
"Roses Contra el Cancer" Foundation
Association "Le cancer du sein, parlons-en!"
Beatriu Pinos Postdoctoral Program
Breast Cancer Research Foundation
Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia
Eileen Stein Jacoby Fund
Finnish Cancer Society
Helsinki University Central Hospital
Marianne and Robert MacDonald Foundation
National Institute for Health Research (UK)
Spanish National Society of Medical Oncology
Transversal Action Against Cancer
05/0612Department of Defense
08/1120FIS
08/1635FIS
08/1359FIS
09/02483FIS
107054German Cancer Aid
145684Australian National Health and Medical Research Council
110663Academy of Finland
2004-3088Dutch Cancer Society
2007-3756Dutch Cancer Society
2009SGR1489AGAUR Catalan Government Agency
2009SGR293AGAUR Catalan Government Agency
223175EU
454508Australian National Health and Medical Research Council
288704Australian National Health and Medical Research Council
4017Associazione Italiana per la Ricerca sul Cancro
AECC 2010Spanish Association Against Cancer
AICR-07-0454Association for International Cancer Research
BCFR U01 CA69398National Institutes of Health
CA113916Specialized Program of Research Excellence (SPORE)
CA122340National Cancer Institute (USA)
CA128978National Cancer Institute (USA)
CA69446National Institutes of Health
CA69467National Institutes of Health
CA69631National Institutes of Health
CA69638National Institutes of Health
C1287/A10118Michael Cuccione Foundation for Childhood Cancer Research, Cancer Research-UK
C1287/A8874Michael Cuccione Foundation for Childhood Cancer Research, Cancer Research-UK
C490/A10119Michael Cuccione Foundation for Childhood Cancer Research, Cancer Research-UK
C5047/A8385Michael Cuccione Foundation for Childhood Cancer Research, Cancer Research-UK
C8197/A10123Michael Cuccione Foundation for Childhood Cancer Research, Cancer Research-UK
CA69417National Institutes of Health
CB07/02/2005Spanish Ministries of Health, and Science ane Innovation
HEALTH-F2-2009-223175EU
INT "5x1000"Fondazione IRCCS Istituto Nazionale Tumori
NKI 1998-1854Dutch Cancer Society
P50 CA83638Specialized Program of Research Excellence (SPORE)
RD06/0020/1060RTICCC
RFA-CA-06-503National Institutes of Health
RFP N02PC45022-46Research Triangle Institute Informatics Support Center
RFPS-2006-3-340203Italian Ministero della Salute
TV93Center for Molecular Medicine Cologne
RBLAO3-BETHItalian Ministero dell'Universita e Ricerca
RD06/0020/0028RTICCC

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