title: Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.
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.
authors: Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute-IDIBELL, L'Hospitalet, Catalonia, Spain. cmaxwell@cfri.ubc.ca
authors: Christopher A
authors: CA
authors: Maxwell
authors: Javier
authors: J
authors: Benítez
authors: Laia
authors: L
authors: Gómez-Baldó
authors: Ana
authors: A
authors: Osorio
authors: Núria
authors: N
authors: Bonifaci
authors: Ricardo
authors: R
authors: Fernández-Ramires
authors: Sylvain V
authors: SV
authors: Costes
authors: Elisabet
authors: E
authors: Guinó
authors: Helen
authors: H
authors: Chen
authors: Gareth J R
authors: GJ
authors: Evans
authors: Pooja
authors: P
authors: Mohan
authors: Isabel
authors: I
authors: Català
authors: Anna
authors: A
authors: Petit
authors: Helena
authors: H
authors: Aguilar
authors: Alberto
authors: A
authors: Villanueva
authors: Alvaro
authors: A
authors: Aytes
authors: Jordi
authors: J
authors: Serra-Musach
authors: Gad
authors: G
authors: Rennert
authors: Flavio
authors: F
authors: Lejbkowicz
authors: Paolo
authors: P
authors: Peterlongo
authors: Siranoush
authors: S
authors: Manoukian
authors: Bernard
authors: B
authors: Peissel
authors: Carla B
authors: CB
authors: Ripamonti
authors: Bernardo
authors: B
authors: Bonanni
authors: Alessandra
authors: A
authors: Viel
authors: Anna
authors: A
authors: Allavena
authors: Loris
authors: L
authors: Bernard
authors: Paolo
authors: P
authors: Radice
authors: Eitan
authors: E
authors: Friedman
authors: Bella
authors: B
authors: Kaufman
authors: Yael
authors: Y
authors: Laitman
authors: Maya
authors: M
authors: Dubrovsky
authors: Roni
authors: R
authors: Milgrom
authors: Anna
authors: A
authors: Jakubowska
authors: Cezary
authors: C
authors: Cybulski
authors: Bohdan
authors: B
authors: Gorski
authors: Katarzyna
authors: K
authors: Jaworska
authors: Katarzyna
authors: K
authors: Durda
authors: Grzegorz
authors: G
authors: Sukiennicki
authors: Jan
authors: J
authors: Lubiński
authors: Yin Yao
authors: YY
authors: Shugart
authors: Susan M
authors: SM
authors: Domchek
authors: Richard
authors: R
authors: Letrero
authors: Barbara L
authors: BL
authors: Weber
authors: Frans B L
authors: FB
authors: Hogervorst
authors: Matti A
authors: MA
authors: Rookus
authors: J Margriet
authors: JM
authors: Collee
authors: Peter
authors: P
authors: Devilee
authors: Marjolijn J
authors: MJ
authors: Ligtenberg
authors: Rob B van der
authors: RB
authors: Luijt
authors: Cora M
authors: CM
authors: Aalfs
authors: Quinten
authors: Q
authors: Waisfisz
authors: Juul
authors: J
authors: Wijnen
authors: Cornelis E P van
authors: CE
authors: Roozendaal
authors: Douglas F
authors: DF
authors: Easton
authors: Susan
authors: S
authors: Peock
authors: Margaret
authors: M
authors: Cook
authors: Clare
authors: C
authors: Oliver
authors: Debra
authors: D
authors: Frost
authors: Patricia
authors: P
authors: Harrington
authors: D Gareth
authors: DG
authors: Evans
authors: Fiona
authors: F
authors: Lalloo
authors: Rosalind
authors: R
authors: Eeles
authors: Louise
authors: L
authors: Izatt
authors: Carol
authors: C
authors: Chu
authors: Diana
authors: D
authors: Eccles
authors: Fiona
authors: F
authors: Douglas
authors: Carole
authors: C
authors: Brewer
authors: Heli
authors: H
authors: Nevanlinna
authors: Tuomas
authors: T
authors: Heikkinen
authors: Fergus J
authors: FJ
authors: Couch
authors: Noralane M
authors: NM
authors: Lindor
authors: Xianshu
authors: X
authors: Wang
authors: Andrew K
authors: AK
authors: Godwin
authors: Maria A
authors: MA
authors: Caligo
authors: Grazia
authors: G
authors: Lombardi
authors: Niklas
authors: N
authors: Loman
authors: Per
authors: P
authors: Karlsson
authors: Hans
authors: H
authors: Ehrencrona
authors: Anna von
authors: Av
authors: Wachenfeldt
authors: Rosa Bjork
authors: RB
authors: Barkardottir
authors: Ute
authors: U
authors: Hamann
authors: Muhammad U
authors: MU
authors: Rashid
authors: Adriana
authors: A
authors: Lasa
authors: Trinidad
authors: T
authors: Caldés
authors: Raquel
authors: R
authors: Andrés
authors: Michael
authors: M
authors: Schmitt
authors: Volker
authors: V
authors: Assmann
authors: Kristen
authors: K
authors: Stevens
authors: Kenneth
authors: K
authors: Offit
authors: João
authors: J
authors: Curado
authors: Hagen
authors: H
authors: Tilgner
authors: Roderic
authors: R
authors: Guigó
authors: Gemma
authors: G
authors: Aiza
authors: Joan
authors: J
authors: Brunet
authors: Joan
authors: J
authors: Castellsagué
authors: Griselda
authors: G
authors: Martrat
authors: Ander
authors: A
authors: Urruticoechea
authors: Ignacio
authors: I
authors: Blanco
authors: Laima
authors: L
authors: Tihomirova
authors: David E
authors: DE
authors: Goldgar
authors: Saundra
authors: S
authors: Buys
authors: Esther M
authors: EM
authors: John
authors: Alexander
authors: A
authors: Miron
authors: Melissa
authors: M
authors: Southey
authors: Mary B
authors: MB
authors: Daly
authors: Rita K
authors: RK
authors: Schmutzler
authors: Barbara
authors: B
authors: Wappenschmidt
authors: Alfons
authors: A
authors: Meindl
authors: Norbert
authors: N
authors: Arnold
authors: Helmut
authors: H
authors: Deissler
authors: Raymonda
authors: R
authors: Varon-Mateeva
authors: Christian
authors: C
authors: Sutter
authors: Dieter
authors: D
authors: Niederacher
authors: Evgeny
authors: E
authors: Imyamitov
authors: Olga M
authors: OM
authors: Sinilnikova
authors: Dominique
authors: D
authors: Stoppa-Lyonne
authors: Sylvie
authors: S
authors: Mazoyer
authors: Carole
authors: C
authors: Verny-Pierre
authors: Laurent
authors: L
authors: Castera
authors: Antoine
authors: A
authors: de Pauw
authors: Yves-Jean
authors: YJ
authors: Bignon
authors: Nancy
authors: N
authors: Uhrhammer
authors: Jean-Philippe
authors: JP
authors: Peyrat
authors: Philippe
authors: P
authors: Vennin
authors: Sandra
authors: S
authors: Fert Ferrer
authors: Marie-Agnès
authors: MA
authors: Collonge-Rame
authors: Isabelle
authors: I
authors: Mortemousque
authors: Amanda B
authors: AB
authors: Spurdle
authors: Jonathan
authors: J
authors: Beesley
authors: Xiaoqing
authors: X
authors: Chen
authors: Sue
authors: S
authors: Healey
authors: Mary Helen
authors: MH
authors: Barcellos-Hoff
authors: Marc
authors: M
authors: Vidal
authors: Stephen B
authors: SB
authors: Gruber
authors: Conxi
authors: C
authors: Lázaro
authors: Gabriel
authors: G
authors: Capellá
authors: Lesley
authors: L
authors: McGuffog
authors: Katherine L
authors: KL
authors: Nathanson
authors: Antonis C
authors: AC
authors: Antoniou
authors: Georgia
authors: G
authors: Chenevix-Trench
authors: Markus C
authors: MC
authors: Fleisch
authors: Víctor
authors: V
authors: Moreno
authors: Miguel Angel
authors: MA
authors: Pujana
mesh_terms: D064096:Aurora Kinase A; D064127:Aurora Kinases; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006367:HeLa Cells; D006579:Heterozygote; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism*; D008870:Microtubules / Q000502:physiology / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000032:analysis
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D011960:Receptors, Estrogen; C098946:hyaluronan-mediated motility receptor; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases