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Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer
11/04/2010
The progesterone derivative MPA triggers in vivo RANKL expression and the proliferation of mammary epithelial cells as well as mammary tumorigenesis through RANK. a, Induction of RANKL expression by MPA. Nulliparous wild-type females were implanted subcutaneously with slow-release MPA pellets or treated with sham surgery. In situ immunostaining of progesterone receptor (PR, red) and RANKL (green) in mammary epithelial cells after treatment with MPA for 3 days. b, Epithelial proliferation in mammary glands of control, littermates and RANKDmam females 3 days after sham treatment and MPA implantation. Proliferation was determined by in situ Ki67 immunostaining. c, Onset of palpable mammary tumours in MMTV-Cre rankfloxed/D females (RANKDmam) (n514) and age-matched littermate control females (n519) treated with MPA pellets and the carcinogen DMBA.
Progestins, used in contraceptives and hormone replacement therapy, have been epidemiographically linked to breast cancer. We have now found a mechanistic basis for this association and could 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. This then triggers uncontrolled proliferation and protection against DNA damage-induced cell death of mammary epithelial cells. Moreover, we could show a crucial role of the RANKL/RANK system in normal stem cell proliferation and expansion during pregnancy as well as in self renewal of tumor-inducing cancer stem cells. These findings were also confirmed by Gonzalez-Suarez et al., who published in a back-to-back paper that inhibition of RANKL reduces tumorigenesis in the same hormone-induced as well as in other mouse mammary gland tumour models, indicating that an anti-RANKL therapy might also proof effective in human trials. Denosumab, a monoclonal anti-RANKL Ab, has already proofen to be effective in treating bone loss in post-menopausal osteoporosis and in cancer patients with skeletal-related symptoms and could therefore be now easily tested in breast cancer patients.
