Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.

Christopher Maxwell 1, 2, * Javier Benítez 3, 4 Laia Gómez-Baldó 1, 2 Ana Osorio 3, 4 Núria Bonifaci 1, 2, 5 Ricardo Fernández-Ramires 3, 4 Sylvain Costes 6 Elisabet Guinó 2, 5 Helen Chen 7 Gareth Evans 7 Pooja Mohan 7 Isabel Català 8 Anna Petit 8 Helena Aguilar 1 Alberto Villanueva 1 Alvaro Aytes 1 Jordi Serra-Musach 1, 5 Gad Rennert 9 Flavio Lejbkowicz 9 Paolo Peterlongo 10 Siranoush Manoukian 11 Bernard Peissel 11 Carla Ripamonti 10, 11 Bernardo Bonanni 12 Alessandra Viel 13 Anna Allavena 14 Loris Bernard 15 Paolo Radice 10 Eitan Friedman 16, 17 Bella Kaufman 16 Yael Laitman 16 Maya Dubrovsky 16 Roni Milgrom 16 Anna Jakubowska 18 Cezary Cybulski 18 Bohdan Gorski 18 Katarzyna Jaworska 18 Katarzyna Durda 18 Grzegorz Sukiennicki 18 Jan Lubiński 18 Yin Yao Shugart 19 Susan Domchek 20 Richard Letrero 20 Barbara Weber 20 Frans Hogervorst 21 Matti Rookus 22 J Margriet Collee 23 Peter Devilee 24 Marjolijn Ligtenberg 25 Rob Van Der Luijt 26 Cora Aalfs 27 Quinten Waisfisz 28 Juul Wijnen 29 Cornelis Van Roozendaal 30 Douglas Easton 31 Susan Peock 31 Margaret Cook 31 Clare Oliver 31 Debra Frost 31 Patricia Harrington 32 D Gareth Evans 33 Fiona Lalloo 33 Rosalind Eeles 34 Louise Izatt 35 Carol Chu 36 Diana Eccles 37 Fiona Douglas 38 Carole Brewer 39 Heli Nevanlinna 40 Tuomas Heikkinen 41 Fergus Couch 42 Noralane Lindor 43 Xianshu Wang 42 Andrew Godwin 44 Maria Caligo 45 Grazia Lombardi 45 Niklas Loman 46 Per Karlsson 47 Hans Ehrencrona 48 Anna Von Wachenfeldt 49 Rosa Bjork Barkardottir 50 Ute Hamann 51 Muhammad Rashid 52, 53 Adriana Lasa 54 Trinidad Caldés 55 Raquel Andrés 56 Michael Schmitt 57 Volker Assmann 58 Kristen Stevens 59 Kenneth Offit 60 João Curado 61 Hagen Tilgner 61 Roderic Guigó 61 Gemma Aiza 1 Joan Brunet 62 Joan Castellsagué 62 Griselda Martrat 1 Ander Urruticoechea 1 Ignacio Blanco 62 Laima Tihomirova 63 David Goldgar 64 Saundra Buys 65 Esther John 66 Alexander Miron 67, 68 Melissa Southey 69 Mary Daly 70 Rita Schmutzler 71 Barbara Wappenschmidt 71 Alfons Meindl 72 Norbert Arnold 73 Helmut Deissler 74 Raymonda Varon-Mateeva 75 Christian Sutter 76 Dieter Niederacher 77 Evgeny Imyamitov 78 Olga Sinilnikova 79, 80 Dominique Stoppa-Lyonnet 81 Sylvie Mazoyer 80 Carole Verny-Pierre 80 Laurent Castera 81 Antoine De Pauw 81 Yves-Jean Bignon 82 Nancy Uhrhammer 82 Jean-Philippe Peyrat 83 Philippe Vennin 84 Sandra Fert Ferrer 85 Marie-Agnès Collonge-Rame 86 Isabelle Mortemousque 87 Amanda Spurdle 88 Jonathan Beesley 88 Xiaoqing Chen 88 Sue Healey 88 Mary Helen Barcellos-Hoff 6 Marc Vidal 89, 90 Stephen Gruber 91 Conxi Lázaro 62 Gabriel Capellá 62 Lesley Mcguffog 31 Katherine Nathanson 20 Antonis Antoniou 31 Georgia Chenevix-Trench 88 Markus Fleisch 92 Víctor Moreno 4, 5 Miguel Angel Pujana 1, 4, 5, *
* Auteur correspondant
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.
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PLoS Biology, Public Library of Science, 2011, 9 (11), pp.e1001199. 〈10.1371/journal.pbio.1001199〉
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Christopher Maxwell, Javier Benítez, Laia Gómez-Baldó, Ana Osorio, Núria Bonifaci, et al.. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.. PLoS Biology, Public Library of Science, 2011, 9 (11), pp.e1001199. 〈10.1371/journal.pbio.1001199〉. 〈inserm-00706872〉

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