| [ Summary ] |
Mice with disruptions of Rank or Rankl exhibit normal mammary development during puberty, but their mammary epithelium fails to proliferate and form lobuloalveolar structures during pregnancy, resulting in the death of newborns. The expression of RANKL is absent in virgin glands, but gradually increases during pregnancy. RANKL expression in mammary epithelial cells is induced by pregnancy related hormones such as prolactin, progesterone and PTHrP. Hormone replacement therapy is associated with an increased risk of breast cancer. In particular, progesterones or their synthetic derivatives (progestins) such as medroxyprogesterone acetate (MPA) markedly increase the risk of abnormal mammograms and breast cancer. Recently, it was revealed that MPA treatment triggers the induction of RANKL expression in progesterone receptor-positive luminal mammary epithelial cells, resulting in autocrine or/and paracrine stimulation of RANK signaling in the mammary epithelium. Importantly, specific deletion of RANK in mammary epithelium cells prevents both the onset and progression of MPA-driven mammary cancer and impairs self-renewal of breast cancer stem cells. In contrast, mammary-specific overexpression of RANK results in the acceleration of preneoplasias of the mammary glands and an increase in mammary tumor formation after either multiparity or treatment with a carcinogen and progestin. Furthermore, interestingly, RANK is highly expressed in several human breast cancer cell lines and primary human breast tumors. Functionally, it has been shown that RANKL can stimulate directed migration of mammary epithelial cells as well as prostate cancer and melanoma cells toward a source of RANKL. In an in vivo metastasis model, OPG reduced the tumor burden in bones and ameliorated clinical paralysis, but did not affect the frequency of the spread of metastases into other tissues. These findings show that the RANKL/RANK system is crucial for breast tumorigenesis and bone metastasis. |