Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer

• Published in: Nature (London) Vol. 468; no. 7320; pp. 98 - 102
• Main Authors: Kenner, Lukas, Khokha, Rama, Lee, Heather J, Schramek, Daniel, Widschwendter, Martin, Joshi, Purna A, Hanada, Reiko, Leibbrandt, Andreas, Glimcher, Laurie, Sigl, Verena, Penninger, Josef M, Schett, Georg, Pospisilik, John A, Pasparakis, Manolis, Aliprantis, Antonios, Ormandy, Christopher J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.11.2010; Nature Publishing Group
• Subjects: 631/208/2489/144/68; 631/250/127/1220; 631/67/1347; Animal tumors. Experimental tumors; Animals; Apoptosis; Apoptosis - radiation effects; Biological and medical sciences; Breast cancer; Cancer; Carcinogenesis; Care and treatment; Cell cycle; Cell Differentiation; Cell Proliferation - drug effects; Complications and side effects; Contraceptives; Development and progression; DNA Damage; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - radiation effects; Experimental genital and mammary tumors; Female; Females; Gamma Rays; Health aspects; Hormone replacement therapy; Hormone therapy; Humanities and Social Sciences; Integrin alpha6 - metabolism; letter; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Mammography; Medical sciences; Medroxyprogesterone; Medroxyprogesterone Acetate - administration & dosage; Medroxyprogesterone Acetate - adverse effects; Mice; multidisciplinary; NF-kappa B - metabolism; Osteoclasts - cytology; Phosphoproteins - analysis; Phosphoproteins - immunology; Prevention; Progestins - administration & dosage; Progestins - adverse effects; Proteins; RANK Ligand - deficiency; RANK Ligand - genetics; RANK Ligand - metabolism; Receptor Activator of Nuclear Factor-kappa B - deficiency; Receptor Activator of Nuclear Factor-kappa B - genetics; Receptor Activator of Nuclear Factor-kappa B - metabolism; Risk factors; Rodents; Science; Science (multidisciplinary); Signal Transduction; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Tumors; Womens health; Austria; Breast disease; Receptor activator Nfkb ligand; Cytokine; Rodentia; Breast cancer; Osteoclast; Malignant tumor; Cell differentiation; Carcinogenesis; Progestagen; Osteoarticular system; Mammary gland diseases; Vertebrata; Mammalia; Cancerology; Mouse; Tumor necrosis factor; Animal; Medroxyprogesterone; Bone; Cancer
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature09387

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- 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 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.