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 Europe1. 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 cancer2,3. 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-κB 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 CD49fhi 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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We thank all members of our laboratories for helpful discussions; G. Forni for providing NeuT transgenic mice. A.O.A. is a recipient of a Career Award for Medical Scientists from the Burroughs Wellcome Fund. L.G. is supported by National Institutes of Health (NIH) grant HD055601. G.S’s work is supported by the German Research Council (Deutsche Forschungsgemeinschaft (DFG): FOR643, SFB641 and SPP1468), by the Interdisciplinary Center for Clinical Sciences Erlangen and by the focus programme SPP1468 (Immunobone) of the DFG and the Masterswitch project of the European Union (EU). C.J.O. is supported by the National Health and Medical Research Council of Australia, the Australian Cancer Research Fund and the Cancer Institute New South Wales. D.S. is supported by the EU InflaCare network. M.W. is supported by a grant from the University College London (UCL) Hospital/UCL Comprehensive Biomedical Research Centre project no. 152, and part of this work was undertaken at UCL Hospital/UCL, which received a proportion of its funding from the Department of Health National Institute for Health Research Biomedical Research Centres funding scheme. J.M.P. is supported by grants from Institute of Molecular Biotechnology, the Austrian Ministry of Sciences, the Austrian Academy of Sciences, GEN-AU (AustroMouse), an EU Marie Curie Excellence Grant, and a European Research Council Advanced Grant. Special thanks go to Limin Zhang, who provided a first idea for this manuscript and died much too early of breast cancer.

Author information

Author notes

    • Daniel Schramek
    •  & Andreas Leibbrandt

    These authors contributed equally to the work.


  1. IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria

    • Daniel Schramek
    • , Andreas Leibbrandt
    • , Verena Sigl
    • , John A. Pospisilik
    • , Reiko Hanada
    •  & Josef M. Penninger
  2. Medical University of Vienna, 1090 Vienna, Austria

    • Lukas Kenner
  3. Garvan Institute of Medical Research, Darlinghurst 2010, Sydney, Australia

    • Heather J. Lee
    •  & Christopher J. Ormandy
  4. Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada

    • Purna A. Joshi
    •  & Rama Khokha
  5. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Department of Medicine, Harvard Medical School and the Ragon Institute of MGH/MIT and Harvard, Boston, Massachusetts 02115, USA

    • Antonios Aliprantis
    •  & Laurie Glimcher
  6. Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster (CECAD), University of Cologne, Zülpicher Strasse 47a, 50674 Cologne, Germany

    • Manolis Pasparakis
  7. Department of Gynaecological Oncology, University College London, London WC1E 6AU, UK

    • Martin Widschwendter
  8. Department of Internal Medicine 3, University of Erlangen-Nuremberg, 91054 Erlangen, Germany

    • Georg Schett


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D.S. performed most experiments together with A.L. (NeuT experiments) and V.S. (experiments with MPA and DMBA). A.L. generated the RANKfloxed mice. L.K. analysed the tumour section as an expert pathologist. R.H. helped with hormone treatment of mice. P.A.J. and R.K. helped with FACS analysis of mammary-stem-cell populations. A.P. helped in gene set enrichments. H.L. and C.J.O. performed the experiments on prolactin receptor mutant mice. L.G., with A.A. and M.P., provided essential mouse strains and input to the paper. G.S. and M.W. helped in human experiments and read the manuscript critically. J.M.P. coordinated the project, wrote the manuscript, and together with D.S. designed the experiments.

Competing interests

J.M.P. declares that IMBA, his host institute, is planning to submit a patent on blocking RANKL/RANK for future treatment/prevention of breast cancer, and that J.M.P. owns shares in Amgen, a company that developed RANKL blocking antibodies. No other competing financial interest is known.

Corresponding author

Correspondence to Josef M. Penninger.

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    Supplementary Information

    This file contains Supplementary Text containing information on Rank detection in tumors and Cre effects and Gene expression profiling. The file also contains Supplementary Figures 1-16 with legends and additional references.

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