Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.
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Authors
Maxwell, Christopher ABenítez, Javier
Gómez-Baldó, Laia
Osorio, Ana
Bonifaci, Núria
Fernández-Ramires, Ricardo
Costes, Sylvain V
Guinó, Elisabet
Chen, Helen
Evans, Gareth J R
Mohan, Pooja
Català, Isabel
Petit, Anna
Aguilar, Helena
Villanueva, Alberto
Aytes, Alvaro
Serra-Musach, Jordi
Rennert, Gad
Lejbkowicz, Flavio
Peterlongo, Paolo
Manoukian, Siranoush
Peissel, Bernard
Ripamonti, Carla B
Bonanni, Bernardo
Viel, Alessandra
Allavena, Anna
Bernard, Loris
Radice, Paolo
Friedman, Eitan
Kaufman, Bella
Laitman, Yael
Dubrovsky, Maya
Milgrom, Roni
Jakubowska, Anna
Cybulski, Cezary
Gorski, Bohdan
Jaworska, Katarzyna
Durda, Katarzyna
Sukiennicki, Grzegorz
Lubiński, Jan
Shugart, Yin Yao
Domchek, Susan M
Letrero, Richard
Weber, Barbara L
Hogervorst, Frans B L
Rookus, Matti A
Collee, J Margriet
Devilee, Peter
Ligtenberg, Marjolijn J
Luijt, Rob B van der
Aalfs, Cora M
Waisfisz, Quinten
Wijnen, Juul
Roozendaal, Cornelis E P van
Easton, Douglas F
Peock, Susan
Cook, Margaret
Oliver, Clare
Frost, Debra
Harrington, Patricia
Evans, D Gareth
Lalloo, Fiona
Eeles, Rosalind
Izatt, Louise
Chu, Carol
Eccles, Diana
Douglas, Fiona
Brewer, Carole
Nevanlinna, Heli
Heikkinen, Tuomas
Couch, Fergus J
Lindor, Noralane M
Wang, Xianshu
Godwin, Andrew K
Caligo, Maria A
Lombardi, Grazia
Loman, Niklas
Karlsson, Per
Ehrencrona, Hans
Wachenfeldt, Anna von
Barkardottir, Rosa Bjork
Hamann, Ute
Rashid, Muhammad U
Lasa, Adriana
Caldés, Trinidad
Andrés, Raquel
Schmitt, Michael
Assmann, Volker
Stevens, Kristen
Offit, Kenneth
Curado, João
Tilgner, Hagen
Guigó, Roderic
Aiza, Gemma
Brunet, Joan
Castellsagué, Joan
Martrat, Griselda
Urruticoechea, Ander
Blanco, Ignacio
Tihomirova, Laima
Goldgar, David E
Buys, Saundra
John, Esther M
Miron, Alexander
Southey, Melissa
Daly, Mary B
Schmutzler, Rita K
Wappenschmidt, Barbara
Meindl, Alfons
Arnold, Norbert
Deissler, Helmut
Varon-Mateeva, Raymonda
Sutter, Christian
Niederacher, Dieter
Imyamitov, Evgeny
Sinilnikova, Olga M
Stoppa-Lyonne, Dominique
Mazoyer, Sylvie
Verny-Pierre, Carole
Castera, Laurent
de Pauw, Antoine
Bignon, Yves-Jean
Uhrhammer, Nancy
Peyrat, Jean-Philippe
Vennin, Philippe
Fert Ferrer, Sandra
Collonge-Rame, Marie-Agnès
Mortemousque, Isabelle
Spurdle, Amanda B
Beesley, Jonathan
Chen, Xiaoqing
Healey, Sue
Barcellos-Hoff, Mary Helen
Vidal, Marc
Gruber, Stephen B
Lázaro, Conxi
Capellá, Gabriel
McGuffog, Lesley
Nathanson, Katherine L
Antoniou, Antonis C
Chenevix-Trench, Georgia
Fleisch, Markus C
Moreno, Víctor
Pujana, Miguel Angel
Issue Date
2011-11
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PLoS Biol. 2011, 9(11):e1001199Abstract
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.Description
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http://dx.doi.org/10.1371/journal.pbio.1001199http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217025/?tool=pubmed
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Archived with thanks to PLoS biologyae974a485f413a2113503eed53cd6c53
10.1371/journal.pbio.1001199
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