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Cell Res. 2016 Jul;26(7):761-74. doi: 10.1038/cr.2016.69. Epub 2016 May 31.

RANKL/RANK control Brca1 mutation- .

Author information

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

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.

PMID:
27241552
PMCID:
PMC5129883
DOI:
10.1038/cr.2016.69
[Indexed for MEDLINE]
Free PMC Article

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