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The osteoclast differentiation factors RANKL/RANK control development of progesterone-driven breast cancer


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. 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. 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-kappaB 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.

Type Journal
ISBN 1476-4687 (Electronic) 0028-0836 (Linking)
Authors Schramek, D.; Leibbrandt, A.; Sigl, V.; Kenner, L.; Pospisilik, J. A.; Lee, H. J.; Hanada, R.; Joshi, P. A.; Aliprantis, A.; Glimcher, L.; Pasparakis, M.; Khokha, R.; Ormandy, C. J.; Widschwendter, M.; Schett, G.; Penninger, J. M.
Publisher Name NATURE
Published Date 2010-11-01
Published Volume 468
Published Issue 7320
Published Pages 98-102
Status Published in-print
DOI nature09387 [pii] 10.1038/nature09387 10.1038/nature09387
URL link to publisher's version
OpenAccess link to author's accepted manuscript version