title: RANKL/RANK control Brca1 mutation- .
abstract: Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients.
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
authors.forename: Verena
authors.initials: V
authors.lastname: Sigl
authors.affiliation: Department of Biological Sciences, University of Maryland-Baltimore County, Baltimore, MD 21250, USA.
authors.forename: Kwadwo
authors.initials: K
authors.lastname: Owusu-Boaitey
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Purna A
authors.initials: PA
authors.lastname: Joshi
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
authors.forename: Anoop
authors.initials: A
authors.lastname: Kavirayani
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Wirnsberger
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Novatchkova
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
authors.forename: Ivona
authors.initials: I
authors.lastname: Kozieradzki
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5.|Department of Molecular Genetics, University of Toronto, Ontario, Canada M5S 3E1.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schramek
authors.affiliation: Department of Biological Sciences, University of Maryland-Baltimore County, Baltimore, MD 21250, USA.
authors.forename: Nnamdi
authors.initials: N
authors.lastname: Edokobi
authors.affiliation: Department of Pharmacology, University of Maryland, Baltimore, School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Hersl
authors.affiliation: Department of Pharmacology, University of Maryland, Baltimore, School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Aishia
authors.initials: A
authors.lastname: Sampson
authors.affiliation: Department of Biological Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Odai-Afotey
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
authors.forename: Conxi
authors.initials: C
authors.lastname: Lazaro
authors.affiliation: Cancer Epigenetics and Biology Program, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Gonzalez-Suarez
authors.affiliation: ProCURE, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pujana
authors.affiliation: Department of Public and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
authors.forename: For
authors.initials: F
authors.lastname: Cimba
authors.affiliation: Cancer Epigenetics and Biology Program, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
authors.forename: Holger
authors.initials: H
authors.lastname: Heyn
authors.affiliation: Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, University Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Enrique
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authors.lastname: Vidal
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 1Z5.
authors.forename: Jennifer
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authors.lastname: Cruickshank
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 1Z5.
authors.forename: Hal
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authors.lastname: Berman
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
authors.forename: Renu
authors.initials: R
authors.lastname: Sarao
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
authors.forename: Melita
authors.initials: M
authors.lastname: Ticevic
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
authors.forename: Iris
authors.initials: I
authors.lastname: Uribesalgo
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
authors.forename: Luigi
authors.initials: L
authors.lastname: Tortola
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
authors.forename: Shuan
authors.initials: S
authors.lastname: Rao
authors.affiliation: Departments of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria.
authors.forename: Yen
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Departments of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Pfeiler
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, USA.
authors.forename: Eva Yhp
authors.initials: EY
authors.lastname: Lee
authors.affiliation: Department of Experimental Pathology and Pathology of Laboratory Animals, Medical University Vienna and University of Veterinary Medicine Vienna, Vienna 1090, Austria.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bago-Horvath
authors.affiliation: Department of Experimental Pathology and Pathology of Laboratory Animals, Medical University Vienna and University of Veterinary Medicine Vienna, Vienna 1090, Austria.|Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: Research Unit Molecular Lung and Pleura Pathology, Institute of Pathology, Medical University Graz, Graz 8010, Austria.
authors.forename: Helmuth
authors.initials: H
authors.lastname: Popper
authors.affiliation: Departments of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Singer
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
authors.affiliation: Department of Pharmacology, University of Maryland, Baltimore, School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Laundette P
authors.initials: LP
authors.lastname: Jones
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D047628:Estrogen Receptor alpha; D053245:RANK Ligand; C517736:Rank-Fc; D053246:Receptor Activator of Nuclear Factor-kappa B; D011980:Receptors, Progesterone; D011993:Recombinant Fusion Proteins; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D016159:Tumor Suppressor Protein p53