Volume 26, No 7, Jul 2016

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 26 Issue 7, July 2016: 761-774   |  Open Access

ORIGINAL ARTICLES

RANKL/RANK control Brca1 mutation-driven mammary tumors

Verena Sigl^1,*, Kwadwo Owusu-Boaitey^2,*, Purna A Joshi³, Anoop Kavirayani¹, Gerald Wirnsberger¹, Maria Novatchkova¹, Ivona Kozieradzki¹, Daniel Schramek^4,5, Nnamdi Edokobi², Jerome Hers^l6, Aishia Sampson⁶, Ashley Odai-Afotey⁷, Conxi Lazaro⁸, Eva Gonzalez-Suarez⁹, Miguel A Pujana¹⁰, for CIMBA¹¹, Holger Heyn⁹, Enrique Vidal¹², Jennifer Cruickshank¹³, Hal Berman¹³, Renu Sarao¹, Melita Ticevic¹, Iris Uribesalgo¹, Luigi Tortola¹, Shuan Rao¹, Yen Tan¹⁴, Georg Pfeiler¹⁴, Eva YHP Lee¹⁵, Zsuzsanna Bago-Horvath¹⁶, Lukas Kenner^16,17, Helmuth Popper¹⁸, Christian Singer¹⁴, Rama Khokha³, Laundette P Jones⁶ and Josef M Penninger¹

¹IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria
²Department of Biological Sciences, University of Maryland-Baltimore County, Baltimore, MD 21250, USA
³Princess Margaret Cancer Centre, Toronto, Ontario, Canada M5G 1L7
⁴Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5
⁵Department of Molecular Genetics, University of Toronto, Ontario, Canada M5S 3E1
⁶Department of Pharmacology, University of Maryland, Baltimore, School of Medicine, Baltimore, MD 21201, USA
⁷Department of Biological Sciences, Cornell University, Ithaca, NY 14853, USA
⁸Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
⁹Cancer Epigenetics and Biology Program, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
¹⁰ProCURE, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
¹¹Department of Public and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
¹²Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, University Pompeu Fabra, Barcelona, Catalonia, Spain
¹³The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 1Z5
¹⁴Departments of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria
¹⁵Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, USA
¹⁶Department of Experimental Pathology and Pathology of Laboratory Animals, Medical University Vienna and University of Veterinary Medicine Vienna, Vienna 1090, Austria
¹⁷Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria
¹⁸Research Unit Molecular Lung and Pleura Pathology, Institute of Pathology, Medical University Graz, Graz 8010, Austria Correspondence: Josef M Penninger, E-mail: josef.penninger@imba.oeaw.ac.at; Laundette P Jones,(LJones@som.umaryland.edu)

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.

10.1038/cr.2016.69

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