Abstract
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-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 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / radiation effects
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Cell Differentiation
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Cell Proliferation / drug effects
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DNA Damage
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Epithelial Cells / radiation effects
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Female
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Gamma Rays
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Integrin alpha6 / metabolism
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Mammary Neoplasms, Experimental / chemically induced*
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / pathology*
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Medroxyprogesterone Acetate / administration & dosage
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Medroxyprogesterone Acetate / adverse effects
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Mice
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NF-kappa B / metabolism
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Osteoclasts / cytology
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Phosphoproteins / analysis
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Phosphoproteins / immunology
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Progestins / administration & dosage
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Progestins / adverse effects*
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RANK Ligand / deficiency
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RANK Ligand / genetics
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RANK Ligand / metabolism*
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Receptor Activator of Nuclear Factor-kappa B / deficiency
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Receptor Activator of Nuclear Factor-kappa B / genetics
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Receptor Activator of Nuclear Factor-kappa B / metabolism
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Signal Transduction
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Stem Cells / cytology
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Stem Cells / drug effects
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Stem Cells / metabolism
Substances
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Integrin alpha6
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NF-kappa B
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Phosphoproteins
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Progestins
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Tnfrsf11a protein, mouse
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Tnfsf11 protein, mouse
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Medroxyprogesterone Acetate