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

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

doi:10.1371/journal.pbio.1001199

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	e1001199
Journal	Plos Biology
Volume	9
Issue number	11
DOIs	https://doi.org/10.1371/journal.pbio.1001199
Publication status	Published - Nov 2011

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10.1371/journal.pbio.1001199Licence: CC BY

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Maxwell, C. A., Benitez, J., Gomez-Baldo, L., Osorio, A., Bonifaci, N., Fernandez-Ramires, R., Costes, S. V., Guino, E., Chen, H., Evans, G. J. R., Mohan, P., Catala, I., Petit, A., Aguilar, H., Villanueva, A., Aytes, A., Serra-Musach, J., Rennert, G., Lejbkowicz, F., ... Angel Pujana, M. (2011). Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer. Plos Biology, 9(11), Article e1001199. https://doi.org/10.1371/journal.pbio.1001199

@article{202c48b9aba3472da5fef658d71345c9,

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.",

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

year = "2011",

month = nov,

doi = "10.1371/journal.pbio.1001199",

language = "English",

volume = "9",

journal = "Plos Biology",

issn = "1544-9173",

publisher = "Public Library of Science",

number = "11",

}

Maxwell, CA, Benitez, J, Gomez-Baldo, L, Osorio, A, Bonifaci, N, Fernandez-Ramires, R, Costes, SV, Guino, E, Chen, H, Evans, GJR, Mohan, P, Catala, I, Petit, A, Aguilar, H, Villanueva, A, Aytes, A, Serra-Musach, J, Rennert, G, Lejbkowicz, F, Peterlongo, P, Manoukian, S, Peissel, B, Ripamonti, CB, Bonanni, B, Viel, A, Allavena, A, Bernard, L, Radice, P, Friedman, E, Kaufman, B, Laitman, Y, Dubrovsky, M, Milgrom, R, Jakubowska, A, Cybulski, C, Gorski, B, Jaworska-Bieniek, K, Durda, K, Sukiennicki, G, Lubinski, J, Shugart, YY, Domchek, SM, Letrero, R, Weber, BL, Hogervorst, FBL, Rookus, MA, Collee, MJ, Devilee, P, Ligtenberg, MJL, van der Luijt, RB, Aalfs, CM, Waisfisz, Q, Wijnen, JT, van Roozendaal, CEP, Easton, DF, Peock, S, Cook, M, Oliver, C, Frost, D, Harrington, P, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Eccles, D, Douglas, F, Brewer, C, Nevanlinna, H, Heikkinen, T, Couch, FJ, Lindor, NM, Wang, X, Godwin, AK, Caligo, MA, Lombardi, G, Loman, N, Karlsson, P, Ehrencrona, H, von Wachenfeldt, A, Barkardottir, RB, Hamann, U, Rashid, MU, Lasa, A, Caldes, T, Andres Conejero, R, Schmitt, M, Assmann, V, Stevens, K, Offit, K, Curado, J, Tilgner, H, Guigo, R, Aiza, G, Brunet, J, Castellsague, J, Martrat, G, Urruticoechea, A, Blanco, I, Tihomirova, L, Goldgar, DE, Buys, S, John, EM, Miron, A, Southey, MC, Daly, MB, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Arnold, N, Deissler, H, Varon-Mateeva, R, Sutter, C, Niederacher, D, Imyamitov, E, Sinilnikova, OM, Stoppa-Lyonne, D, Mazoyer, S, Verny-Pierre, C, Castera, L, de Pauw, A, Bignon, Y-J, Uhrhammer, N, Peyrat, J-P, Vennin, P, Ferrer, SF, Collonge-Rame, M-A, Mortemousque, I, Spurdle, AB, Beesley, J, Chen, X, Healey, S, Barcellos-Hoff, MH, Vidal, M, Gruber, SB, Lazaro, C, Capella Munar, G, McGuffog, L, Nathanson, KL, Antoniou, AC, Chenevix-Trench, G, Fleisch, MC, Moreno, V & Angel Pujana, M 2011, 'Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer', Plos Biology, vol. 9, no. 11, e1001199. https://doi.org/10.1371/journal.pbio.1001199

TY - JOUR

T1 - Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer

AU - Maxwell, Christopher A.

AU - Benitez, Javier

AU - Gomez-Baldo, Laia

AU - Osorio, Ana

AU - Bonifaci, Nuria

AU - Fernandez-Ramires, Ricardo

AU - Costes, Sylvain V.

AU - Guino, Elisabet

AU - Chen, Helen

AU - Evans, Gareth J. R.

AU - Mohan, Pooja

AU - Catala, 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-Bieniek, Katarzyna

AU - Durda, Katarzyna

AU - Sukiennicki, Grzegorz

AU - Lubinski, 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, Margriet J.

AU - Devilee, Peter

AU - Ligtenberg, Marjolijn J. L.

AU - van der Luijt, Rob B.

AU - Aalfs, Cora M.

AU - Waisfisz, Quinten

AU - Wijnen, Juul T.

AU - van Roozendaal, Cornelis E. P.

AU - Easton, Douglas F.

AU - Peock, Susan

AU - Cook, Margaret

AU - Oliver, Clare

AU - Frost, Debra

AU - Harrington, Patricia

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 - von Wachenfeldt, Anna

AU - Barkardottir, Rosa Bjork

AU - Hamann, Ute

AU - Rashid, Muhammad U.

AU - Lasa, Adriana

AU - Caldes, Trinidad

AU - Andres Conejero, Raquel

AU - Schmitt, Michael

AU - Assmann, Volker

AU - Stevens, Kristen

AU - Offit, Kenneth

AU - Curado, Joao

AU - Tilgner, Hagen

AU - Guigo, Roderic

AU - Aiza, Gemma

AU - Brunet, Joan

AU - Castellsague, 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 C.

AU - Daly, Mary B.

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 - Ferrer, Sandra Fert

AU - Collonge-Rame, Marie-Agnes

AU - Mortemousque, Isabelle

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 - Lazaro, Conxi

AU - Capella Munar, Gabriel

AU - McGuffog, Lesley

AU - Nathanson, Katherine L.

AU - Antoniou, Antonis C.

AU - Chenevix-Trench, Georgia

AU - Fleisch, Markus C.

AU - Moreno, Victor

AU - Angel Pujana, Miguel

PY - 2011/11

Y1 - 2011/11

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.

U2 - 10.1371/journal.pbio.1001199

DO - 10.1371/journal.pbio.1001199

M3 - Article

C2 - 22110403

SN - 1544-9173

VL - 9

JO - Plos Biology

JF - Plos Biology

IS - 11

M1 - e1001199

ER -