Maxwell, Christopher A., Benitez, Javier, Gomez-Baldo, Laia, Osorio, Ana ORCID: 0000-0001-8124-3984, Bonifaci, Nuria, Fernandez-Ramires, Ricardo, Costes, Sylvain V., Guino, Elisabet ORCID: 0000-0003-0093-2652, Chen, Helen, Evans, Gareth J. R., Mohan, Pooja, Catala, Isabel, Petit, Anna, Aguilar, Helena, Villanueva, Alberto, Aytes, Alvaro ORCID: 0000-0003-0725-5340, Serra-Musach, Jordi, Rennert, Gad, Lejbkowicz, Flavio, Peterlongo, Paolo ORCID: 0000-0001-6951-6855, Manoukian, Siranoush, Peissel, Bernard ORCID: 0000-0001-9233-3571, Ripamonti, Carla B., Bonanni, Bernardo, Viel, Alessandra ORCID: 0000-0003-2804-0840, Allavena, Anna, Bernard, Loris, Radice, Paolo ORCID: 0000-0001-6298-4111, Friedman, Eitan, Kaufman, Bella, Laitman, Yael, Dubrovsky, Maya, Milgrom, Roni, Jakubowska, Anna ORCID: 0000-0002-5650-0501, Cybulski, Cezary, Gorski, Bohdan, Jaworska, Katarzyna, Durda, Katarzyna, Sukiennicki, Grzegorz, Lubinski, Jan ORCID: 0000-0003-2931-3003, 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., van der Luijt, Rob B., Aalfs, Cora M., Waisfisz, Quinten, Wijnen, Juul, van Roozendaal, Cornelis E. P., Easton, Douglas F., Peock, Susan, Cook, Margaret, Oliver, Clare, Frost, Debra, Harrington, Patricia, Evans, D. Gareth, Lalloo, Fiona, Eeles, Rosalind ORCID: 0000-0002-3698-6241, Izatt, Louise, Chu, Carol, Eccles, Diana, Douglas, Fiona, Brewer, Carole, Nevanlinna, Heli ORCID: 0000-0002-0916-2976, Heikkinen, Tuomas ORCID: 0000-0003-1154-6204, Couch, Fergus J., Lindor, Noralane M., Wang, Xianshu, Godwin, Andrew K., Caligo, Maria A., Lombardi, Grazia, Loman, Niklas, Karlsson, Per, Ehrencrona, Hans ORCID: 0000-0002-5589-3622, von Wachenfeldt, Anna, Barkardottir, Rosa Bjork, Hamann, Ute, Rashid, Muhammad U., Lasa, Adriana ORCID: 0000-0001-9957-9646, Caldes, Trinidad, Andres, Raquel, Schmitt, Michael, Assmann, Volker, Stevens, Kristen, Offit, Kenneth, Curado, Joao ORCID: 0000-0003-3916-0936, Tilgner, Hagen, Guigo, Roderic, Aiza, Gemma, Brunet, Joan ORCID: 0000-0003-1945-3512, Castellsague, Joan, Martrat, Griselda, Urruticoechea, Ander ORCID: 0000-0003-0359-3641, Blanco, Ignacio ORCID: 0000-0002-7414-7481, Tihomirova, Laima, Goldgar, David E., Buys, Saundra, John, Esther M., Miron, Alexander, Southey, Melissa ORCID: 0000-0002-6313-9005, Daly, Mary B., Schmutzler, Rita K., Wappenschmidt, Barbara, Meindl, Alfons, Arnold, Norbert ORCID: 0000-0003-4523-8808, Deissler, Helmut, Varon-Mateeva, Raymonda, Sutter, Christian, Niederacher, Dieter, Imyamitov, Evgeny, Sinilnikova, Olga M., Stoppa-Lyonne, Dominique, Mazoyer, Sylvie ORCID: 0000-0002-2135-0160, Verny-Pierre, Carole, Castera, Laurent ORCID: 0000-0002-0459-3400, de Pauw, Antoine, Bignon, Yves-Jean, Uhrhammer, Nancy, Peyrat, Jean-Philippe, Vennin, Philippe, Ferrer, Sandra Fert, Collonge-Rame, Marie-Agnes, Mortemousque, Isabelle, Spurdle, Amanda B., Beesley, Jonathan ORCID: 0000-0003-1942-325X, Chen, Xiaoqing, Healey, Sue, Barcellos-Hoff, Mary Helen, Vidal, Marc, Gruber, Stephen B., Lazaro, Conxi, Capella, Gabriel ORCID: 0000-0002-4669-7320, McGuffog, Lesley, Nathanson, Katherine L., Antoniou, Antonis C., Chenevix-Trench, Georgia ORCID: 0000-0002-1878-2587, Fleisch, Markus C., Moreno, Victor ORCID: 0000-0002-2818-5487 and Angel Pujana, Miguel (2011). Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer. PLoS. Biol., 9 (11). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1545-7885

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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 (wHR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, wHR = 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Maxwell, Christopher A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benitez, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gomez-Baldo, LaiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Osorio, AnaUNSPECIFIEDorcid.org/0000-0001-8124-3984UNSPECIFIED
Bonifaci, NuriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez-Ramires, RicardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Costes, Sylvain V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guino, ElisabetUNSPECIFIEDorcid.org/0000-0003-0093-2652UNSPECIFIED
Chen, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Evans, Gareth J. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohan, PoojaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Catala, IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petit, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aguilar, HelenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Villanueva, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aytes, AlvaroUNSPECIFIEDorcid.org/0000-0003-0725-5340UNSPECIFIED
Serra-Musach, JordiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rennert, GadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lejbkowicz, FlavioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peterlongo, PaoloUNSPECIFIEDorcid.org/0000-0001-6951-6855UNSPECIFIED
Manoukian, SiranoushUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peissel, BernardUNSPECIFIEDorcid.org/0000-0001-9233-3571UNSPECIFIED
Ripamonti, Carla B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonanni, BernardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Viel, AlessandraUNSPECIFIEDorcid.org/0000-0003-2804-0840UNSPECIFIED
Allavena, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bernard, LorisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radice, PaoloUNSPECIFIEDorcid.org/0000-0001-6298-4111UNSPECIFIED
Friedman, EitanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaufman, BellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laitman, YaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dubrovsky, MayaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milgrom, RoniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jakubowska, AnnaUNSPECIFIEDorcid.org/0000-0002-5650-0501UNSPECIFIED
Cybulski, CezaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gorski, BohdanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jaworska, KatarzynaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Durda, KatarzynaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sukiennicki, GrzegorzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lubinski, JanUNSPECIFIEDorcid.org/0000-0003-2931-3003UNSPECIFIED
Shugart, Yin YaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domchek, Susan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Letrero, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, Barbara L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hogervorst, Frans B. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rookus, Matti A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Collee, J. MargrietUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devilee, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ligtenberg, Marjolijn J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Luijt, Rob B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aalfs, Cora M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waisfisz, QuintenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wijnen, JuulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Roozendaal, Cornelis E. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Easton, Douglas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peock, SusanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cook, MargaretUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oliver, ClareUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frost, DebraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harrington, PatriciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Evans, D. GarethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lalloo, FionaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eeles, RosalindUNSPECIFIEDorcid.org/0000-0002-3698-6241UNSPECIFIED
Izatt, LouiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chu, CarolUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eccles, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Douglas, FionaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brewer, CaroleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nevanlinna, HeliUNSPECIFIEDorcid.org/0000-0002-0916-2976UNSPECIFIED
Heikkinen, TuomasUNSPECIFIEDorcid.org/0000-0003-1154-6204UNSPECIFIED
Couch, Fergus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindor, Noralane M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, XianshuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Godwin, Andrew K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caligo, Maria A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lombardi, GraziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loman, NiklasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karlsson, PerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ehrencrona, HansUNSPECIFIEDorcid.org/0000-0002-5589-3622UNSPECIFIED
von Wachenfeldt, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barkardottir, Rosa BjorkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamann, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rashid, Muhammad U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lasa, AdrianaUNSPECIFIEDorcid.org/0000-0001-9957-9646UNSPECIFIED
Caldes, TrinidadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andres, RaquelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Assmann, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stevens, KristenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Offit, KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Curado, JoaoUNSPECIFIEDorcid.org/0000-0003-3916-0936UNSPECIFIED
Tilgner, HagenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guigo, RodericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aiza, GemmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunet, JoanUNSPECIFIEDorcid.org/0000-0003-1945-3512UNSPECIFIED
Castellsague, JoanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martrat, GriseldaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Urruticoechea, AnderUNSPECIFIEDorcid.org/0000-0003-0359-3641UNSPECIFIED
Blanco, IgnacioUNSPECIFIEDorcid.org/0000-0002-7414-7481UNSPECIFIED
Tihomirova, LaimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldgar, David E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buys, SaundraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
John, Esther M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miron, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Southey, MelissaUNSPECIFIEDorcid.org/0000-0002-6313-9005UNSPECIFIED
Daly, Mary B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wappenschmidt, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meindl, AlfonsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arnold, NorbertUNSPECIFIEDorcid.org/0000-0003-4523-8808UNSPECIFIED
Deissler, HelmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varon-Mateeva, RaymondaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sutter, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niederacher, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Imyamitov, EvgenyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sinilnikova, Olga M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoppa-Lyonne, DominiqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mazoyer, SylvieUNSPECIFIEDorcid.org/0000-0002-2135-0160UNSPECIFIED
Verny-Pierre, CaroleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Castera, LaurentUNSPECIFIEDorcid.org/0000-0002-0459-3400UNSPECIFIED
de Pauw, AntoineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bignon, Yves-JeanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uhrhammer, NancyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peyrat, Jean-PhilippeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vennin, PhilippeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferrer, Sandra FertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Collonge-Rame, Marie-AgnesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mortemousque, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beesley, JonathanUNSPECIFIEDorcid.org/0000-0003-1942-325XUNSPECIFIED
Chen, XiaoqingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Healey, SueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barcellos-Hoff, Mary HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vidal, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gruber, Stephen B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lazaro, ConxiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Capella, GabrielUNSPECIFIEDorcid.org/0000-0002-4669-7320UNSPECIFIED
McGuffog, LesleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nathanson, Katherine L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antoniou, Antonis C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chenevix-Trench, GeorgiaUNSPECIFIEDorcid.org/0000-0002-1878-2587UNSPECIFIED
Fleisch, Markus C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moreno, VictorUNSPECIFIEDorcid.org/0000-0002-2818-5487UNSPECIFIED
Angel Pujana, MiguelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-486808
DOI: 10.1371/journal.pbio.1001199
Journal or Publication Title: PLoS. Biol.
Volume: 9
Number: 11
Date: 2011
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1545-7885
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CENTROSOMAL MICROTUBULE NUCLEATION; PROGENITOR-CELL FATE; MUTATION CARRIERS; MAMMARY-GLAND; MITOTIC SPINDLE; STEM-CELLS; MULTIPLE-MYELOMA; BRCA1-DEPENDENT UBIQUITINATION; EXPRESSION SIGNATURE; ADHERENS JUNCTIONSMultiple languages
Biochemistry & Molecular Biology; BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48680

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