Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.
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...
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Public Library of Science (PLoS)
2011
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Biology (General) QH301-705.5 |
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Biology (General) QH301-705.5 Christopher A Maxwell Javier Benítez Laia Gómez-Baldó Ana Osorio Núria Bonifaci Ricardo Fernández-Ramires Sylvain V Costes Elisabet Guinó Helen Chen Gareth J R Evans Pooja Mohan Isabel Català 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 Katarzyna Durda Grzegorz Sukiennicki Jan Lubiński Yin Yao Shugart Susan M Domchek Richard Letrero Barbara L Weber Frans B L Hogervorst Matti A Rookus J Margriet Collee Peter Devilee Marjolijn J Ligtenberg Rob B van der Luijt Cora M Aalfs Quinten Waisfisz Juul Wijnen Cornelis E P van Roozendaal HEBON EMBRACE Douglas F Easton Susan Peock Margaret Cook Clare Oliver Debra Frost Patricia Harrington D Gareth Evans 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 SWE-BRCA Rosa Bjork Barkardottir Ute Hamann Muhammad U Rashid Adriana Lasa Trinidad Caldés Raquel Andrés Michael Schmitt Volker Assmann Kristen Stevens Kenneth Offit João Curado Hagen Tilgner Roderic Guigó Gemma Aiza Joan Brunet Joan Castellsagué Griselda Martrat Ander Urruticoechea Ignacio Blanco Laima Tihomirova David E Goldgar Saundra Buys Esther M John Alexander Miron Melissa Southey Mary B Daly BCFR 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-Agnès Collonge-Rame Isabelle Mortemousque GEMO Study Collaborators Amanda B Spurdle Jonathan Beesley Xiaoqing Chen Sue Healey kConFab Mary Helen Barcellos-Hoff Marc Vidal Stephen B Gruber Conxi Lázaro Gabriel Capellá Lesley McGuffog Katherine L Nathanson Antonis C Antoniou Georgia Chenevix-Trench Markus C Fleisch Víctor Moreno Miguel Angel Pujana Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. |
| description |
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. |
| format |
article |
| author |
Christopher A Maxwell Javier Benítez Laia Gómez-Baldó Ana Osorio Núria Bonifaci Ricardo Fernández-Ramires Sylvain V Costes Elisabet Guinó Helen Chen Gareth J R Evans Pooja Mohan Isabel Català 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 Katarzyna Durda Grzegorz Sukiennicki Jan Lubiński Yin Yao Shugart Susan M Domchek Richard Letrero Barbara L Weber Frans B L Hogervorst Matti A Rookus J Margriet Collee Peter Devilee Marjolijn J Ligtenberg Rob B van der Luijt Cora M Aalfs Quinten Waisfisz Juul Wijnen Cornelis E P van Roozendaal HEBON EMBRACE Douglas F Easton Susan Peock Margaret Cook Clare Oliver Debra Frost Patricia Harrington D Gareth Evans 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 SWE-BRCA Rosa Bjork Barkardottir Ute Hamann Muhammad U Rashid Adriana Lasa Trinidad Caldés Raquel Andrés Michael Schmitt Volker Assmann Kristen Stevens Kenneth Offit João Curado Hagen Tilgner Roderic Guigó Gemma Aiza Joan Brunet Joan Castellsagué Griselda Martrat Ander Urruticoechea Ignacio Blanco Laima Tihomirova David E Goldgar Saundra Buys Esther M John Alexander Miron Melissa Southey Mary B Daly BCFR 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-Agnès Collonge-Rame Isabelle Mortemousque GEMO Study Collaborators Amanda B Spurdle Jonathan Beesley Xiaoqing Chen Sue Healey kConFab Mary Helen Barcellos-Hoff Marc Vidal Stephen B Gruber Conxi Lázaro Gabriel Capellá Lesley McGuffog Katherine L Nathanson Antonis C Antoniou Georgia Chenevix-Trench Markus C Fleisch Víctor Moreno Miguel Angel Pujana |
| author_facet |
Christopher A Maxwell Javier Benítez Laia Gómez-Baldó Ana Osorio Núria Bonifaci Ricardo Fernández-Ramires Sylvain V Costes Elisabet Guinó Helen Chen Gareth J R Evans Pooja Mohan Isabel Català 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 Katarzyna Durda Grzegorz Sukiennicki Jan Lubiński Yin Yao Shugart Susan M Domchek Richard Letrero Barbara L Weber Frans B L Hogervorst Matti A Rookus J Margriet Collee Peter Devilee Marjolijn J Ligtenberg Rob B van der Luijt Cora M Aalfs Quinten Waisfisz Juul Wijnen Cornelis E P van Roozendaal HEBON EMBRACE Douglas F Easton Susan Peock Margaret Cook Clare Oliver Debra Frost Patricia Harrington D Gareth Evans 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 SWE-BRCA Rosa Bjork Barkardottir Ute Hamann Muhammad U Rashid Adriana Lasa Trinidad Caldés Raquel Andrés Michael Schmitt Volker Assmann Kristen Stevens Kenneth Offit João Curado Hagen Tilgner Roderic Guigó Gemma Aiza Joan Brunet Joan Castellsagué Griselda Martrat Ander Urruticoechea Ignacio Blanco Laima Tihomirova David E Goldgar Saundra Buys Esther M John Alexander Miron Melissa Southey Mary B Daly BCFR 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-Agnès Collonge-Rame Isabelle Mortemousque GEMO Study Collaborators Amanda B Spurdle Jonathan Beesley Xiaoqing Chen Sue Healey kConFab Mary Helen Barcellos-Hoff Marc Vidal Stephen B Gruber Conxi Lázaro Gabriel Capellá Lesley McGuffog Katherine L Nathanson Antonis C Antoniou Georgia Chenevix-Trench Markus C Fleisch Víctor Moreno Miguel Angel Pujana |
| author_sort |
Christopher A Maxwell |
| title |
Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. |
| title_short |
Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. |
| title_full |
Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. |
| title_fullStr |
Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. |
| title_full_unstemmed |
Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. |
| title_sort |
interplay between brca1 and rhamm regulates epithelial apicobasal polarization and may influence risk of breast cancer. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/6b575e23a5b6401b9e491335b8001395 |
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oai:doaj.org-article:6b575e23a5b6401b9e491335b80013952021-11-18T05:36:53ZInterplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.1544-91731545-788510.1371/journal.pbio.1001199https://doaj.org/article/6b575e23a5b6401b9e491335b80013952011-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22110403/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Differentiated 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.Christopher A MaxwellJavier BenítezLaia Gómez-BaldóAna OsorioNúria BonifaciRicardo Fernández-RamiresSylvain V CostesElisabet GuinóHelen ChenGareth J R EvansPooja MohanIsabel CatalàAnna PetitHelena AguilarAlberto VillanuevaAlvaro AytesJordi Serra-MusachGad RennertFlavio LejbkowiczPaolo PeterlongoSiranoush ManoukianBernard PeisselCarla B RipamontiBernardo BonanniAlessandra VielAnna AllavenaLoris BernardPaolo RadiceEitan FriedmanBella KaufmanYael LaitmanMaya DubrovskyRoni MilgromAnna JakubowskaCezary CybulskiBohdan GorskiKatarzyna JaworskaKatarzyna DurdaGrzegorz SukiennickiJan LubińskiYin Yao ShugartSusan M DomchekRichard LetreroBarbara L WeberFrans B L HogervorstMatti A RookusJ Margriet ColleePeter DevileeMarjolijn J LigtenbergRob B van der LuijtCora M AalfsQuinten WaisfiszJuul WijnenCornelis E P van RoozendaalHEBONEMBRACEDouglas F EastonSusan PeockMargaret CookClare OliverDebra FrostPatricia HarringtonD Gareth EvansFiona LallooRosalind EelesLouise IzattCarol ChuDiana EcclesFiona DouglasCarole BrewerHeli NevanlinnaTuomas HeikkinenFergus J CouchNoralane M LindorXianshu WangAndrew K GodwinMaria A CaligoGrazia LombardiNiklas LomanPer KarlssonHans EhrencronaAnna von WachenfeldtSWE-BRCARosa Bjork BarkardottirUte HamannMuhammad U RashidAdriana LasaTrinidad CaldésRaquel AndrésMichael SchmittVolker AssmannKristen StevensKenneth OffitJoão CuradoHagen TilgnerRoderic GuigóGemma AizaJoan BrunetJoan CastellsaguéGriselda MartratAnder UrruticoecheaIgnacio BlancoLaima TihomirovaDavid E GoldgarSaundra BuysEsther M JohnAlexander MironMelissa SoutheyMary B DalyBCFRRita K SchmutzlerBarbara WappenschmidtAlfons MeindlNorbert ArnoldHelmut DeisslerRaymonda Varon-MateevaChristian SutterDieter NiederacherEvgeny ImyamitovOlga M SinilnikovaDominique Stoppa-LyonneSylvie MazoyerCarole Verny-PierreLaurent CasteraAntoine de PauwYves-Jean BignonNancy UhrhammerJean-Philippe PeyratPhilippe VenninSandra Fert FerrerMarie-Agnès Collonge-RameIsabelle MortemousqueGEMO Study CollaboratorsAmanda B SpurdleJonathan BeesleyXiaoqing ChenSue HealeykConFabMary Helen Barcellos-HoffMarc VidalStephen B GruberConxi LázaroGabriel CapelláLesley McGuffogKatherine L NathansonAntonis C AntoniouGeorgia Chenevix-TrenchMarkus C FleischVíctor MorenoMiguel Angel PujanaPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 9, Iss 11, p e1001199 (2011) |