Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.
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Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. / Maxwell, Christopher A; Benítez, Javier; Gómez-Baldó, Laia; Osorio, Ana; Bonifaci, Núria; Fernández-Ramires, Ricardo; Costes, Sylvain V; Guinó, Elisabet; Chen, Helen; Evans, Gareth J R; Mohan, Pooja; Català, Isabel; Petit, Anna; Aguilar, Helena; Villanueva, Alberto; Aytes, Alvaro; Serra-Musach, Jordi; Rennert, Gad; Lejbkowicz, Flavio; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Ripamonti, Carla B; Bonanni, Bernardo; Viel, Alessandra; Allavena, Anna; Bernard, Loris; Radice, Paolo; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Dubrovsky, Maya; Milgrom, Roni; Jakubowska, Anna; Cybulski, Cezary; Gorski, Bohdan; Jaworska, Katarzyna; Durda, Katarzyna; Sukiennicki, Grzegorz; Lubiński, Jan; 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; Luijt, Rob B van der; Aalfs, Cora M; Waisfisz, Quinten; Wijnen, Juul; Roozendaal, Cornelis E P van; HEBON, [Unbekannt]; EMBRACE, [Unbekannt]; Easton, Douglas F; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Harrington, Patricia; Evans, D Gareth; Lalloo, Fiona; Eeles, Rosalind; Izatt, Louise; Chu, Carol; Eccles, Diana; Douglas, Fiona; Brewer, Carole; Nevanlinna, Heli; Heikkinen, Tuomas; Couch, Fergus J; Lindor, Noralane M; Wang, Xianshu; Godwin, Andrew K; Caligo, Maria A; Lombardi, Grazia; Loman, Niklas; Karlsson, Per; Ehrencrona, Hans; Wachenfeldt, Anna von; SWE-BRCA, [Unbekannt]; Barkardottir, Rosa Bjork; Hamann, Ute; Rashid, Muhammad U; Lasa, Adriana; Caldés, Trinidad; Andrés, Raquel; Schmitt, Michael; Assmann, Volker; Stevens, Kristen; Offit, Kenneth; Curado, João; Tilgner, Hagen; Guigó, Roderic; Aiza, Gemma; Brunet, Joan; Castellsagué, Joan; Martrat, Griselda; Urruticoechea, Ander; Blanco, Ignacio; Tihomirova, Laima; Goldgar, David E; Buys, Saundra; John, Esther M; Miron, Alexander; Southey, Melissa; Daly, Mary B; BCFR, [Unbekannt]; Schmutzler, Rita K; Wappenschmidt, Barbara; Meindl, Alfons; Arnold, Norbert; Deissler, Helmut; Varon-Mateeva, Raymonda; Sutter, Christian; Niederacher, Dieter; Imyamitov, Evgeny; Sinilnikova, Olga M; Stoppa-Lyonne, Dominique; Mazoyer, Sylvie; Verny-Pierre, Carole; Castera, Laurent; de Pauw, Antoine; Bignon, Yves-Jean; Uhrhammer, Nancy; Peyrat, Jean-Philippe; Vennin, Philippe; Sandra, Fert Ferrer; Collonge-Rame, Marie-Agnès; Mortemousque, Isabelle; Collaborators, GEMO Study; Spurdle, Amanda B; Beesley, Jonathan; Chen, Xiaoqing; Healey, Sue; Barcellos-Hoff, Mary Helen; Vidal, Marc; Gruber, Stephen B; Lázaro, Conxi; Capellá, Gabriel; McGuffog, Lesley; Nathanson, Katherine L; Antoniou, Antonis C; Chenevix-Trench, Georgia; Fleisch, Markus C; Moreno, Víctor; Pujana, Miguel Angel.
in: PLOS BIOL, Jahrgang 9, Nr. 11, 11, 2011, S. 1001199.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.
AU - Maxwell, Christopher A
AU - Benítez, Javier
AU - Gómez-Baldó, Laia
AU - Osorio, Ana
AU - Bonifaci, Núria
AU - Fernández-Ramires, Ricardo
AU - Costes, Sylvain V
AU - Guinó, Elisabet
AU - Chen, Helen
AU - Evans, Gareth J R
AU - Mohan, Pooja
AU - Català, Isabel
AU - Petit, Anna
AU - Aguilar, Helena
AU - Villanueva, Alberto
AU - Aytes, Alvaro
AU - Serra-Musach, Jordi
AU - Rennert, Gad
AU - Lejbkowicz, Flavio
AU - Peterlongo, Paolo
AU - Manoukian, Siranoush
AU - Peissel, Bernard
AU - Ripamonti, Carla B
AU - Bonanni, Bernardo
AU - Viel, Alessandra
AU - Allavena, Anna
AU - Bernard, Loris
AU - Radice, Paolo
AU - Friedman, Eitan
AU - Kaufman, Bella
AU - Laitman, Yael
AU - Dubrovsky, Maya
AU - Milgrom, Roni
AU - Jakubowska, Anna
AU - Cybulski, Cezary
AU - Gorski, Bohdan
AU - Jaworska, Katarzyna
AU - Durda, Katarzyna
AU - Sukiennicki, Grzegorz
AU - Lubiński, Jan
AU - Shugart, Yin Yao
AU - Domchek, Susan M
AU - Letrero, Richard
AU - Weber, Barbara L
AU - Hogervorst, Frans B L
AU - Rookus, Matti A
AU - Collee, J Margriet
AU - Devilee, Peter
AU - Ligtenberg, Marjolijn J
AU - Luijt, Rob B van der
AU - Aalfs, Cora M
AU - Waisfisz, Quinten
AU - Wijnen, Juul
AU - Roozendaal, Cornelis E P van
AU - HEBON, [Unbekannt]
AU - EMBRACE, [Unbekannt]
AU - Easton, Douglas F
AU - Peock, Susan
AU - Cook, Margaret
AU - Oliver, Clare
AU - Frost, Debra
AU - Harrington, Patricia
AU - Evans, D Gareth
AU - Lalloo, Fiona
AU - Eeles, Rosalind
AU - Izatt, Louise
AU - Chu, Carol
AU - Eccles, Diana
AU - Douglas, Fiona
AU - Brewer, Carole
AU - Nevanlinna, Heli
AU - Heikkinen, Tuomas
AU - Couch, Fergus J
AU - Lindor, Noralane M
AU - Wang, Xianshu
AU - Godwin, Andrew K
AU - Caligo, Maria A
AU - Lombardi, Grazia
AU - Loman, Niklas
AU - Karlsson, Per
AU - Ehrencrona, Hans
AU - Wachenfeldt, Anna von
AU - SWE-BRCA, [Unbekannt]
AU - Barkardottir, Rosa Bjork
AU - Hamann, Ute
AU - Rashid, Muhammad U
AU - Lasa, Adriana
AU - Caldés, Trinidad
AU - Andrés, Raquel
AU - Schmitt, Michael
AU - Assmann, Volker
AU - Stevens, Kristen
AU - Offit, Kenneth
AU - Curado, João
AU - Tilgner, Hagen
AU - Guigó, Roderic
AU - Aiza, Gemma
AU - Brunet, Joan
AU - Castellsagué, Joan
AU - Martrat, Griselda
AU - Urruticoechea, Ander
AU - Blanco, Ignacio
AU - Tihomirova, Laima
AU - Goldgar, David E
AU - Buys, Saundra
AU - John, Esther M
AU - Miron, Alexander
AU - Southey, Melissa
AU - Daly, Mary B
AU - BCFR, [Unbekannt]
AU - Schmutzler, Rita K
AU - Wappenschmidt, Barbara
AU - Meindl, Alfons
AU - Arnold, Norbert
AU - Deissler, Helmut
AU - Varon-Mateeva, Raymonda
AU - Sutter, Christian
AU - Niederacher, Dieter
AU - Imyamitov, Evgeny
AU - Sinilnikova, Olga M
AU - Stoppa-Lyonne, Dominique
AU - Mazoyer, Sylvie
AU - Verny-Pierre, Carole
AU - Castera, Laurent
AU - de Pauw, Antoine
AU - Bignon, Yves-Jean
AU - Uhrhammer, Nancy
AU - Peyrat, Jean-Philippe
AU - Vennin, Philippe
AU - Sandra, Fert Ferrer
AU - Collonge-Rame, Marie-Agnès
AU - Mortemousque, Isabelle
AU - Collaborators, GEMO Study
AU - Spurdle, Amanda B
AU - Beesley, Jonathan
AU - Chen, Xiaoqing
AU - Healey, Sue
AU - Barcellos-Hoff, Mary Helen
AU - Vidal, Marc
AU - Gruber, Stephen B
AU - Lázaro, Conxi
AU - Capellá, Gabriel
AU - McGuffog, Lesley
AU - Nathanson, Katherine L
AU - Antoniou, Antonis C
AU - Chenevix-Trench, Georgia
AU - Fleisch, Markus C
AU - Moreno, Víctor
AU - Pujana, Miguel Angel
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Humans
KW - Female
KW - Genotype
KW - Genetic Predisposition to Disease
KW - Cell Line, Tumor
KW - Heterozygote
KW - Genetic Variation
KW - Hela Cells
KW - Genes, BRCA1
KW - Genes, BRCA2
KW - Antigens, CD44/genetics/metabolism
KW - BRCA1 Protein/genetics/metabolism
KW - BRCA2 Protein/genetics/metabolism
KW - Breast/cytology
KW - Breast Neoplasms/genetics/metabolism/pathology
KW - Cell Polarity/genetics
KW - Epithelial Cells/cytology/metabolism
KW - Extracellular Matrix Proteins/genetics/metabolism
KW - Microtubules/physiology/ultrastructure
KW - Protein-Serine-Threonine Kinases/metabolism
KW - Receptors, Estrogen/analysis
KW - Humans
KW - Female
KW - Genotype
KW - Genetic Predisposition to Disease
KW - Cell Line, Tumor
KW - Heterozygote
KW - Genetic Variation
KW - Hela Cells
KW - Genes, BRCA1
KW - Genes, BRCA2
KW - Antigens, CD44/genetics/metabolism
KW - BRCA1 Protein/genetics/metabolism
KW - BRCA2 Protein/genetics/metabolism
KW - Breast/cytology
KW - Breast Neoplasms/genetics/metabolism/pathology
KW - Cell Polarity/genetics
KW - Epithelial Cells/cytology/metabolism
KW - Extracellular Matrix Proteins/genetics/metabolism
KW - Microtubules/physiology/ultrastructure
KW - Protein-Serine-Threonine Kinases/metabolism
KW - Receptors, Estrogen/analysis
U2 - 10.1371/journal.pbio.1001199
DO - 10.1371/journal.pbio.1001199
M3 - SCORING: Journal article
VL - 9
SP - 1001199
JO - PLOS BIOL
JF - PLOS BIOL
SN - 1544-9173
IS - 11
M1 - 11
ER -