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Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer

Maxwell, Christopher A.; Benitez, Javier; Gomez-Baldo, Laia; Osorio, Ana; Bonifaci, Nuria; Fernandez-Ramires, Ricardo; Costes, Sylvain V.; Guino, Elisabet; Chen, Helen and Evans, Gareth J. R., et al. (2011) In PLoS Biology 9(11).
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... (More)
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. (Less)
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Genetic Predisposition to Disease, BRCA2, BRCA1, Genes, Female, Extracellular Matrix Proteins, Epithelial Cells, Cell Polarity, Tumor, Cell Line, Breast Neoplasms, Breast, BRCA2 Protein, CD44, Antigens, BRCA1 Protein, Genetic Variation, Genotype, HeLa Cells, Heterozygote, Humans, Microtubules, Protein-Serine-Threonine Kinases, Receptors, Estrogen
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PLoS Biology
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9
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11
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Public Library of Science
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  • scopus:82455175797
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1544-9173
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10.1371/journal.pbio.1001199
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English
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@article{d0d3004b-b1de-4b6c-bae9-a9dcd7640311,
  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.},
  author       = {Maxwell, Christopher A. and Benitez, Javier and Gomez-Baldo, Laia and Osorio, Ana and Bonifaci, Nuria and Fernandez-Ramires, Ricardo and Costes, Sylvain V. and Guino, Elisabet and Chen, Helen and Evans, Gareth J. R. and Mohan, Pooja and Catala, Isabel and Petit, Anna and Aguilar, Helena and Villanueva, Alberto and Aytes, Alvaro and Serra-Musach, Jordi and Rennert, Gad and Lejbkowicz, Flavio and Peterlongo, Paolo and Manoukian, Siranoush and Peissel, Bernard and Ripamonti, Carla B. and Bonanni, Bernardo and Viel, Alessandra and Allavena, Anna and Bernard, Loris and Radice, Paolo and Friedman, Eitan and Kaufman, Bella and Laitman, Yael and Dubrovsky, Maya and Milgrom, Roni and Jakubowska, Anna and Cybulski, Cezary and Gorski, Bohdan and Jaworska, Katarzyna and Durda, Katarzyna and Sukiennicki, Grzegorz and Lubinski, Jan and Shugart, Yin Yao and Domchek, Susan M. and Letrero, Richard and Weber, Barbara L. and Hogervorst, Frans B. L. and Rookus, Matti A. and Collee, J. Margriet and Devilee, Peter and Ligtenberg, Marjolijn J. and van der Luijt, Rob B. and Aalfs, Cora M. and Waisfisz, Quinten and Wijnen, Juul and van Roozendaal, Cornelis E. P. and Easton, Douglas F. and Peock, Susan and Cook, Margaret and Oliver, Clare and Frost, Debra and Harrington, Patricia and Evans, D. Gareth and Lalloo, Fiona and Eeles, Rosalind and Izatt, Louise and Chu, Carol and Eccles, Diana and Douglas, Fiona and Brewer, Carole and Nevanlinna, Heli and Heikkinen, Tuomas and Couch, Fergus J. and Lindor, Noralane M. and Wang, Xianshu and Godwin, Andrew K. and Caligo, Maria A. and Lombardi, Grazia and Loman, Niklas and Karlsson, Per and Ehrencrona, Hans and von Wachenfeldt, Anna and Barkardottir, Rosa Bjork and Hamann, Ute and Rashid, Muhammad U. and Lasa, Adriana and Caldes, Trinidad and Andres, Raquel and Schmitt, Michael and Assmann, Volker and Stevens, Kristen and Offit, Kenneth and Curado, Joao and Tilgner, Hagen and Guigo, Roderic and Aiza, Gemma and Brunet, Joan and Castellsague, Joan and Martrat, Griselda and Urruticoechea, Ander and Blanco, Ignacio and Tihomirova, Laima and Goldgar, David E. and Buys, Saundra and John, Esther M. and Miron, Alexander and Southey, Melissa and Daly, Mary B. and Schmutzler, Rita K. and Wappenschmidt, Barbara and Meindl, Alfons and Arnold, Norbert and Deissler, Helmut and Varon-Mateeva, Raymonda and Sutter, Christian and Niederacher, Dieter and Imyamitov, Evgeny and Sinilnikova, Olga M. and Stoppa-Lyonne, Dominique and Mazoyer, Sylvie and Verny-Pierre, Carole and Castera, Laurent and de Pauw, Antoine and Bignon, Yves-Jean and Uhrhammer, Nancy and Peyrat, Jean-Philippe and Vennin, Philippe and Ferrer, Sandra Fert and Collonge-Rame, Marie-Agnes and Mortemousque, Isabelle and Spurdle, Amanda B. and Beesley, Jonathan and Chen, Xiaoqing and Healey, Sue and Barcellos-Hoff, Mary Helen and Vidal, Marc and Gruber, Stephen B. and Lazaro, Conxi and Capella, Gabriel and McGuffog, Lesley and Nathanson, Katherine L. and Antoniou, Antonis C. and Chenevix-Trench, Georgia and Fleisch, Markus C. and Moreno, Victor and Angel Pujana, Miguel},
  issn         = {1544-9173},
  keyword      = {Genetic Predisposition to Disease,BRCA2,BRCA1,Genes,Female,Extracellular Matrix Proteins,Epithelial Cells,Cell Polarity,Tumor,Cell Line,Breast Neoplasms,Breast,BRCA2 Protein,CD44,Antigens,BRCA1 Protein,Genetic Variation,Genotype,HeLa Cells,Heterozygote,Humans,Microtubules,Protein-Serine-Threonine Kinases,Receptors,Estrogen},
  language     = {eng},
  number       = {11},
  publisher    = {Public Library of Science},
  series       = {PLoS Biology},
  title        = {Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer},
  url          = {http://dx.doi.org/10.1371/journal.pbio.1001199},
  volume       = {9},
  year         = {2011},
}