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

Authors :
Christopher A Maxwell
Javier Benítez
Laia Gómez-Baldó
Ana Osorio
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
Alvaro Aytes
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 Gorski
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 Collee
Peter Devilee
Marjolijn J Ligtenberg
Rob B van der Luijt
Cora M Aalfs
Quinten Waisfisz
Juul Wijnen
Cornelis E P van Roozendaal
HEBON
EMBRACE
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
SWE-BRCA
Rosa Bjork Barkardottir
Ute Hamann
Muhammad U Rashid
Adriana Lasa
Trinidad Caldés
Raquel Andrés
Michael Schmitt
Volker Assmann
Kristen 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 Buys
Esther M John
Alexander Miron
Melissa Southey
Mary B Daly
BCFR
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-Agnès Collonge-Rame
Isabelle Mortemousque
GEMO Study Collaborators
Amanda B Spurdle
Jonathan Beesley
Xiaoqing Chen
Sue Healey
kConFab
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
Víctor Moreno
Miguel Angel Pujana
Source :
PLoS Biology, Vol 9, Iss 11, p e1001199 (2011)
Publication Year :
2011
Publisher :
Public Library of Science (PLoS), 2011.

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.

Subjects

Subjects :
Biology (General)
QH301-705.5

Details

Language :
English
ISSN :
15449173 and 15457885
Volume :
9
Issue :
11
Database :
Directory of Open Access Journals
Journal :
PLoS Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.6b575e23a5b6401b9e491335b8001395
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pbio.1001199