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

2011; Public Library of Science; Volume: 9; Issue: 11 Linguagem: Inglês

10.1371/journal.pbio.1001199

1545-7885

Christopher A. Maxwell, Javier Benítez, Laia Gómez‐Baldó, Ana Osório, Núria Bonifaci, Ricardo Fernández‐Ramires, Sylvain V. Costes, Elisabet Guinó, Helen Chen, Gareth J. R. Evans, Pooja Mohan, Isabel Català, Anna Petit, Helena Aguilar, Alberto Villanueva, Àlvaro Aytés, Jordi Serra-Musach, Gad Rennert, Flavio Lejbkowicz, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Carla B. Ripamonti, Bernardo Bonanni, Alessandra Viel, Anna Allavena, Loris Bernard, Paolo Radice, Eitan Friedman, Bella Kaufman, Yael Laitman, Maya Dubrovsky, Roni Milgrom, Anna Jakubowska, Cezary Cybulski, Bohdan Górski, Katarzyna Jaworska, Katarzyna Durda, Grzegorz Sukiennicki, Jan Lubiński, Yin Yao Shugart, Susan M. Domchek, Richard Letrero, Barbara L. Weber, Frans B.L. Hogervorst, Matti A. Rookus, J. Margriet Collée, Peter Devilee, Marjolijn J. L. Ligtenberg, Rob B. van der Luijt, Cora M. Aalfs, Quinten Waisfisz, Juul Wijnen, C. E. P. van Roozendaal, Douglas F. Easton, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Patricia Harrington, D. Gareth Evans, Fiona Lalloo, Rosalind A. Eeles, Louise Izatt, Carol Chu, Diana Eccles, Fiona Douglas, Carole Brewer, Heli Nevanlinna, Tuomas Heikkinen, Fergus J. Couch, Noralane M. Lindor, Xianshu Wang, Andrew K. Godwin, Maria A. Caligo, Grazia Lombardi, Niklas Loman, Per Karlsson, Hans Ehrencrona, Anna von Wachenfeldt, Rósa B. Barkardóttir, Ute Hamann, Muhammad Usman Rashid, Adriana Lasa, Miguel de la Hoya, Raquel Andrés, Michael Schmitt, Volker Assmann, Kristen N. Stevens, Kenneth Offit, João Curado, Hagen Tilgner, Roderic Guigó, Gemma Aiza, Joan Brunet, Joan Castellsagué, Griselda Martrat, Ander Urruticoechea, Ignacio Blanco, Laima Tihomirova, David E. Goldgar, Saundra S. Buys, Esther M. John, Alexander Miron, Melissa C. Southey, Mary B. Daly, Rita K. Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Norbert Arnold, Helmut Deißler, Raymonda Varon‐Mateeva, Christian Sutter, Dieter Niederacher, Evgeny Imyamitov, Olga M. Sinilnikova, Dominique Stoppa-Lyonne, Sylvie Mazoyer, Carole Verny-Pierre, Laurent Castéra, Antoine de Pauw, Yves–Jean Bignon, Nancy Uhrhammer, J P Peyrat, Philippe Vennin, Sandra Fert Ferrer, Marie-Agnès Collonge-Rame, Isabelle Mortemousque, Amanda B. Spurdle, Jonathan Beesley, Xiaoqing Chen, Sue Healey, Mary Helen Barcellos‐Hoff, Marc Vidal, Stephen B. Gruber, Conxi Lázaro, Gabriel Capellá, Lesley McGuffog, Katherine L. Nathanson, Antonis C. Antoniou, Georgia Chenevix‐Trench, Markus C. Fleisch, Vı́ctor Moreno, Miguel Angel Pujana,

Microtubule and mitosis dynamics

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), ptrend = 0.017; and n = 3,965, wHR = 1.04 (95% CI 0.94–1.16), ptrend = 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.