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

Christopher A. Maxwell*, Javier Benitez, Laia Gomez-Baldo, Ana Osorio, Nuria Bonifaci, Ricardo Fernandez-Ramires, Sylvain V. Costes, Elisabet Guino, Helen Chen, Gareth J. R. Evans, Pooja Mohan, Isabel Catala, Anna Petit, Helena Aguilar, Alberto Villanueva, Alvaro Aytes, Jordi Serra-Musach, Gad Rennert, Flavio Lejbkowicz, Paolo PeterlongoSiranoush 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 Gorski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Grzegorz Sukiennicki, Jan Lubinski, Yin Yao Shugart, Susan M. Domchek, Richard Letrero, Barbara L. Weber, Frans B. L. Hogervorst, Matti A. Rookus, Margriet J. Collee, Peter Devilee, Marjolijn J. L. Ligtenberg, Rob B. van der Luijt, Cora M. Aalfs, Quinten Waisfisz, Juul T. Wijnen, Cornelis E. P. van Roozendaal, Douglas F. Easton, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Patricia Harrington, D. Gareth Evans, Fiona Lalloo, Rosalind 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, Rosa Bjork Barkardottir, Ute Hamann, Muhammad U. Rashid, Adriana Lasa, Trinidad Caldes, Raquel Andres Conejero, Michael Schmitt, Volker Assmann, Kristen Stevens, Kenneth Offit, Joao Curado, Hagen Tilgner, Roderic Guigo, Gemma Aiza, Joan Brunet, Joan Castellsague, Griselda Martrat, Ander Urruticoechea, Ignacio Blanco, Laima Tihomirova, David E. Goldgar, Saundra 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 Castera, Antoine de Pauw, Yves-Jean Bignon, Nancy Uhrhammer, Jean-Philippe Peyrat, Philippe Vennin, Sandra Fert Ferrer, Marie-Agnes Collonge-Rame, Isabelle Mortemousque, Amanda B. Spurdle, Jonathan Beesley, Xiaoqing Chen, Sue Healey, Mary Helen Barcellos-Hoff, Marc Vidal, Stephen B. Gruber, Conxi Lazaro, Gabriel Capella Munar, Lesley McGuffog, Katherine L. Nathanson, Antonis C. Antoniou, Georgia Chenevix-Trench, Markus C. Fleisch, Victor Moreno, Miguel Angel Pujana

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 ((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.
Original languageEnglish
Article numbere1001199
JournalPlos Biology
Volume9
Issue number11
DOIs
Publication statusPublished - Nov 2011

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