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

Abstract

Progestins, used in contraceptives and hormone replacement therapy, have been linked to breast cancer. Two teams working independently have now found a mechanistic basis for this association. Schramek et al. show in a mouse model that synthetic progestins can promote mammary tumour formation by inducing the osteoclast differentiation factor RANKL, which acts on mammary epithelial cells through the RANKL receptor RANK. Gonzalez-Suarez et al. find that inhibition of RANKL reduces tumorigenesis in hormone-induced as well as in other mouse mammary gland tumour models, suggesting a new therapeutic approach. One RANKL inhibitor (denosumab) is in clinical trials as a treatment for bone loss in post-menopausal osteoporosis and for the treatment of skeletal-related symptoms in metastatic bone disease. Progestins, used in contraceptives and hormone replacement therapy, have been linked to breast cancer. These authors provide a mechanistic basis for this association. They show in a mouse model that synthetic progestins can promote mammary tumour formation by inducing RANKL (receptor activator of NF-KB ligand), which acts on mammary epithelial cells through the RANKL receptor RANK. 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.