Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer
November 04, 2010
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.
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