The University of Southampton
University of Southampton Institutional Repository

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

Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer
Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer
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
1544-9173
e1001199-[18pp]
Ashworth, Alan
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Maxwell, Christopher A.
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Ashworth, Alan, Maxwell, Christopher A. and Benítez, Javier et al. (2011) Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. PLoS Biology, 9 (11), e1001199-[18pp]. (doi:10.1371/journal.pbio.1001199). (PMID:22110403)

Record type: Article

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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Accepted/In Press date: 10 October 2011
Published date: 15 November 2011
Organisations: Cancer Sciences

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Local EPrints ID: 383095
URI: https://eprints.soton.ac.uk/id/eprint/383095
ISSN: 1544-9173
PURE UUID: 52f13cd5-92df-4422-8cda-b34a1d35b620

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Date deposited: 20 Oct 2015 13:26
Last modified: 04 Nov 2019 20:08

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Contributors

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

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