Journal
NATURE
Volume 468, Issue 7320, Pages 98-+Publisher
NATURE RESEARCH
DOI: 10.1038/nature09387
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Funding
- Burroughs Wellcome Fund
- National Institutes of Health (NIH) [HD055601]
- German Research Council (Deutsche Forschungsgemeinschaft (DFG)) [FOR643, SFB641, SPP1468]
- Interdisciplinary Center for Clinical Sciences Erlangen
- European Union (EU)
- National Health and Medical Research Council of Australia
- Australian Cancer Research Fund
- Cancer Institute New South Wales
- EU InflaCare network
- University College London (UCL) Hospital/UCL Comprehensive Biomedical Research Centre [152]
- Department of Health National Institute for Health Research Biomedical Research Centres
- Institute of Molecular Biotechnology
- Austrian Ministry of Sciences
- Austrian Academy of Sciences
- GEN-AU (AustroMouse)
- European Research Council
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Breast cancer is one of the most common cancers in humans and will on average affect up to one in eight women in their lifetime in the United States and Europe(1). The Women's Health Initiative and the Million Women Study have shown that hormone replacement therapy is associated with an increased risk of incident and fatal breast cancer(2,3). In particular, synthetic progesterone derivatives (progestins) such as medroxyprogesterone acetate (MPA), used in millions of women for hormone replacement therapy and contraceptives, markedly increase the risk of developing breast cancer. Here we show that the in vivo administration of MPA triggers massive induction of the key osteoclast differentiation factor RANKL (receptor activator of NF-kappa B ligand) in mammary-gland epithelial cells. Genetic inactivation of the RANKL receptor RANK in mammary-gland epithelial cells prevents MPA-induced epithelial proliferation, impairs expansion of the CD49f(hi) stem-cell-enriched population, and sensitizes these cells to DNA-damage-induced cell death. Deletion of RANK from the mammary epithelium results in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. These data show that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer.
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