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

Author

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., Peterlongo, P., Manoukian, S., Peissel, B., Ripamonti, C.B., 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, K., Durda, K., Sukiennicki, G., Lubinski, J., Shugart, Y.Y., Domchek, S.M., Letrero, R., Weber, B.L., Hogervorst, F.B.L., Rookus, M.A., Collee, J.M., Devilee, P., Ligtenberg, M.J., Luijt, R.B. van der, Aalfs, C.M., Waisfisz, Q., Wijnen, J., Roozendaal, C.E.P. van, Easton, D.F., Peock, S., Cook, M., Oliver, C., Frost, D., Harrington, P., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Chu, C., Eccles, D., Douglas, F., Brewer, C., Nevanlinna, H., Heikkinen, T., Couch, F.J., Lindor, N.M., Wang, X.S., Godwin, A.K., Caligo, M.A., Lombardi, G., Loman, N., Karlsson, P., Ehrencrona, H., Wachenfeldt, A. von, Barkardottir, R.B., Hamann, U., Rashid, M.U., Lasa, A., Caldes, T., Andres, 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, D.E., Buys, S., John, E.M., Miron, A., Southey, M., Daly, M.B., Schmutzler, R.K., Wappenschmidt, B., Meindl, A., Arnold, N., Deissler, H., Varon-Mateeva, R., Sutter, C., Niederacher, D., Imyamitov, E., Sinilnikova, O.M., Stoppa-Lyonne, D., Mazoyer, S., Verny-Pierre, C., Castera, L., Pauw, A. de, Bignon, Y.J., Uhrhammer, N., Peyrat, J.P., Vennin, P., Ferrer, S.F., Collonge-Rame, M.A., Mortemousque, I., Spurdle, A.B., Beesley, J., Chen, X.Q., Healey, S., Barcellos-Hoff, M.H., Vidal, M., Gruber, S.B., Lazaro, C., Capella, G., McGuffog, L., Nathanson, K.L., Antoniou, A.C., Chenevix-Trench, G., Fleisch, M.C., Moreno, V., Pujana, M.A., HEBON, EMBRACE, SWE-BRCA, BCFR, GEMO Study Collaborators, kConFab, Human genetics, CCA - Innovative therapy, Universitat de Barcelona, Faculteit der Geneeskunde, Translational Research Laboratory, Catalan Institute of Oncology-Bellvitge Institute for Biomedical Research, Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Catalan Institute of Oncology, Human Genetics Group, Spanish National Cancer Research Centre, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Biomarkers and Susceptibility Unit, Life Science Division [LBNL Berkeley], Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Child and Family Research Institute, Department of Pathology, University Hospital of Bellvitge, Department of Community Medicine and Epidemiology, CHS National Cancer Control Center, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Division of Cancer Prevention and Genetics, Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, Department of Genetics, Biology and Biochemistry, University of Turin, Department of Experimental Oncology, Istituto Europeo di Oncologia-Consortium for Genomics Technology (Cogentech), The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Department of Genetics and Pathology, Pomeranian Medical University-International Hereditary Cancer Centre, Unit of Statistical Genetics, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health, Abramson Cancer Center, University of Pennsylvania [Philadelphia], Family Cancer Clinic, Netherlands Cancer Institute, Department of Epidemiology, Department of Clinical Genetics, Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Department of Genetic Epidemiology, Leiden University Medical Center (LUMC), Department of Human Genetics, Radboud university [Nijmegen], Department of Clinical Molecular Genetics, University Medical Center [Utrecht], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), VU University Medical Center [Amsterdam], Center for Human and Clinical Genetics, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Department of Oncology, Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Yorkshire Regional Genetics Service, St James's hospital, Wessex Clinical Genetics Service, Princess Anne Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Royal Devon & Exeter Hospital, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Laboratory Medicine and Pathology, Mayo Clinic, Department of Medical Genetics, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Lawrence], Section of Genetic Oncology, Pisa University Hospital-University of Pisa - Università di Pisa, Lund University Hospital, Sahlgrenska University Hospital [Gothenburg], Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Karolinska University Hospital [Stockholm], Landspitali-University Hospital, Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Deutsches Krebsforschungszentrum, Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Servicio de Genética, Hospital de la Santa Creu i Sant Pau, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Medical Oncology Division, Hospital Clínico de Zaragoza, Department of Internal Medicine III, University of Rostock, Center for Experimental Medicine, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE)-Institute of Tumor Biology, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Bioinformatics and Genomics Group, Centre for Genomic Regulation (CRG), Genetic Counseling and Hereditary Cancer Programme, Latvian Biomedical Research and Study Centre [Rīga], Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Department of Internal Medicine, Huntsman Cancer Institute, Cancer Prevention Institute of California, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] (HMS), entre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne, Division of Population Science, Fox Chase Cancer Center, Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), Universitätsklinikum Ulm - University Hospital of Ulm, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Heidelberg University Hospital [Heidelberg], University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], N. N. Petrov Institute of Oncology, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Génétique moléculaire, signalisation et cancer (GMSC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Pathologie moléculaire des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncogénétique, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Consultation d'Oncogénétique, Laboratoire de Génétique Chromosomique, Hôtel-Dieu-CH Chambéry, Département de Génétique et Reproduction, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Queensland Institute of Medical Research, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute [Boston]-Department of Cancer Biology, Department of Genetics [Boston], Department of Internal Medicine, Epidemiology, Human Genetics, Department of Obstetrics and Gynaecologie, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], This work was funded by the Spanish Ministries of Health, and Science ane Innovation (CB07/02/2005, FIS 08/1120, 08/1359, 08/1635, and 09/02483, RTICCC RD06/0020/1060 and RD06/0020/0028, Transversal Action Against Cancer, the Spanish Biomedical Research Centre Networks for Epidemiology and Public Health, and Rare Diseases, and the 'Ramón y Cajal' Young Investigator Program), the Spanish National Society of Medical Oncology (2010), the Spanish Association Against Cancer (AECC 2010), the AGAUR Catalan Government Agency (2009SGR1489 and 2009SGR293, and the Beatriu Pinós Postdoctoral Program), the Ramón Areces Foundation (XV), the 'Roses Contra el Càncer' Foundation, the Michael Cuccione Foundation for Childhood Cancer Research, Cancer Research-UK (C490/A10119, C1287/A8874, C1287/A10118, C5047/A8385, and C8197/A10123), the National Institute for Health Research (UK), the Association for International Cancer Research (AICR-07-0454), the Ligue National Contre le Cancer (France), the Association 'Le cancer du sein, parlons-en!', the Dutch Cancer Society (NKI 1998-1854, 2004-3088, and 2007-3756), the Fondazione Italiana per la Ricerca sul Cancro ('Hereditary Tumors'), the Associazione Italiana per la Ricerca sul Cancro (4017), the Italian Ministero della Salute (RFPS-2006-3-340203 and 'Progetto Tumori Femminili'), the Italian Ministero dell'Universita' e Ricerca (RBLAO3-BETH), the Fondazione IRCCS Istituto Nazionale Tumori (INT '5×1000'), the Fondazione Cassa di Risparmio di Pisa (Istituto Toscano Tumori), the National Breast Cancer Foundation (Australia), the Australian National Health and Medical Research Council (145684, 288704, and 454508), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, the Cancer Foundation of Western Australia, the German Cancer Aid (107054), the Center for Molecular Medicine Cologne (TV93), the National Cancer Institute (USA, CA128978 and CA122340), National Institutes of Health (RFA-CA-06-503, BCFR U01 CA69398, CA69417, CA69446, CA69467, CA69631, and CA69638), the Research Triangle Institute Informatics Support Center (RFP N02PC45022-46), the Specialized Program of Research Excellence (SPORE P50 CA83638 and CA113916), the Department of Defense Breast Cancer Research Program (05/0612), the Eileen Stein Jacoby Fund, the Breast Cancer Research Foundation, the Marianne and Robert MacDonald Foundation, the Komen Foundation, the Helsinki University Central Hospital Research Fund, the Academy of Finland (110663), the Finnish Cancer Society, the Sigrid Juselius Foundation, and the EU FP7 (223175, HEALTH-F2-2009-223175)., HEBON, EMBRACE, SWE-BRCA, BCFR, GEMO Study Collaborators, kConFab, Human Genetics, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Università degli studi di Torino = University of Turin (UNITO), Tel Aviv University (TAU), International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), University of Pennsylvania, Universiteit Leiden-Universiteit Leiden, Radboud University [Nijmegen], University of Kansas Medical Center [Kansas City, KS, USA], Uppsala University, Université de Lille-UNICANCER-Université de Lille-UNICANCER, Autard, Delphine, Neurology, and Pathology

Subjects
Mama -- Càncer -- Aspectes genètics, MESH: Extracellular Matrix Proteins, endocrine system diseases, Cellular differentiation, Genes, BRCA2, Genes, BRCA1, Microtubules, MESH: Genotype, 0302 clinical medicine, Breast cancer, Aurora Kinases, MESH: Genetic Variation, Biology (General), skin and connective tissue diseases, 0303 health sciences, Extracellular Matrix Proteins, Tumor, MESH: Microtubules, Cancer Risk Factors, 3. Good health, Hyaluronan Receptors, Oncology, Receptors, Estrogen, MESH: Epithelial Cells, 030220 oncology & carcinogenesis, MESH: Receptors, Estrogen, Medicine, General Agricultural and Biological Sciences, Genotype, QH301-705.5, MESH: Antigens, CD44, General Biochemistry, Genetics and Molecular Biology, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, Genetics, Cancer Genetics, Humans, Progenitor cell, Biology, MESH: BRCA1 Protein, MESH: Humans, CD44, Genetic Variation, Epithelial Cells, Oncogenes, medicine.disease, BRCA1, BRCA2, Genes, Carcinogenesis, MESH: Genes, BRCA1, MESH: Female, MESH: Genes, BRCA2, Population Genetics, HeLa Cells, Epithelial cells, medicine.disease_cause, MESH: BRCA2 Protein, Cell polarity, Basic Cancer Research, Receptors, Breast, MESH: Breast, MESH: Heterozygote, Aurora Kinase A, Cèl·lules epitelials, biology, BRCA1 Protein, General Neuroscience, MESH: Genetic Predisposition to Disease, Cell Polarity, Biological Sciences, BRCA2 Protein, Mama -- Càncer -- Aspectes moleculars, Protein-Serine-Threonine Kinases, Female, Stem cell, MESH: Cell Polarity, Research Article, Oncogens, Heterozygote, MESH: Cell Line, Tumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Protein Serine-Threonine Kinases, Cell Line, Càncer de mama, Cell Line, Tumor, Regulació genètica, medicine, Genetic Predisposition to Disease, Antigens, 030304 developmental biology, General Immunology and Microbiology, Human Genetics, Estrogen, MESH: HeLa Cells, Genetics of Disease, biology.protein, Cancer research, Gene Function, MESH: Breast Neoplasms
Abstract

Genetic analysis identifies the HMMR gene as a modifier of the breast cancer risk associated with BRCA1 gene mutation, while cell biological analysis of the protein product suggests a function in regulating development of the mammary gland., 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), ptrend = 0.017; and n = 3,965, wHR = 1.04 (95% CI 0.94–1.16), ptrend = 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 Summary Mutations in two genes that were initially identified as predisposing carriers to early-onset breast cancer, BRCA1 and BRCA2, cause similar perturbations in cellular responses to DNA damage but predispose carriers to distinct tumor types. Thus, the two genes may trigger different carcinogenic processes. We have used genetic analyses of affected families to uncover additional genetic variation that is linked to the risk of developing cancer for carriers of BRCA1 mutations. This variation falls within a centrosomal gene, named HMMR. The protein product of HMMR, which is called RHAMM, works in concert with BRCA1 to regulate the structure of normal breast cells as they grow and become polarized. This polarization process depends upon a balance between the activities of BRCA1 and the Aurora kinase A, with the kinase opposing BRCA1 function and promoting growth. Our findings provide new insights into the mechanism through which BRCA1 may promote commitment of initially bipotent mammary cells towards the luminal lineage, and how loss of this function may predispose cells to become breast tumors of a basal-like type.

Published
2011
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3. Multicentric neoadjuvant pilot Phase II study of cetuximab combined with docetaxel in operable triple negative breast cancer.

Author

Nabholtz, J.M., Chalabi, N., Radosevic‐Robin, N., Dauplat, M.M., Mouret‐Reynier, M.A., Van Praagh, I., Servent, V., Jacquin, JP, Benmammar, K.E., Kullab, S., Bahadoor, M.R.K., Kwiatkowski, F., Cayre, A., Abrial, C., Durando, X., Bignon, Y.J., Chollet, P., and Penault‐Llorca, F.

Abstract

Systemic therapy for triple negative breast cancer (TNBC) is mostly based upon chemotherapy. Epithelial Growth Factor Receptor (EGFR) is overexpressed in around 50% of TNBC and may play a role in its pathogenesis. Consequently, we performed a multicentric pilot Phase II neoadjuvant trial of cetuximab (anti-EGFR antibody) combined with docetaxel for patients with operable, Stage II-III TNBC. Therapy consisted of weekly cetuximab (first infusion: 400 mg/m2, then 250 mg/m2) combined with six cycles of docetaxel (T: 100 mg/m2) q.3 weeks. Subsequently, all patients underwent surgery. The primary endpoint was pathological complete response (pCR) while clinical response, toxicity and ancillary studies were secondary endpoints. Paraffin-embedded and frozen tumor samples were systematically collected in order to identify predictive biomarkers of efficacy and resistance. From a total of 35 accrued patients, 25 were assessable for pathologic response. The pCR rate was 24% [95% CI: 7.3-40.7]. Complete clinical response rate (cCR) was observed in 22% of cases. Conservative surgery was performed in 75% of patients. Toxicity, mostly cutaneous and hematologic, was manageable. The pre-therapy ratio between CD8+ and FOXP3+ tumor-infiltrating lymphocytes equal or higher than 2.75 was predictive of pCR: 43% versus 0%, p = 0.047. Cetuximab in combination with docetaxel displays a modest activity, but acceptable toxicity as neoadjuvant therapy of operable TNBC. Similarly to previous observations using panitumumab, another anti-EGFR antibody, the immune component of the tumor microenvironment may play an important role in predicting TNBC response to the neoadjuvant therapy. [ABSTRACT FROM AUTHOR]

Published
2016
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