Receptor activator of NF-κB (RANK) is expressed on several human prostate and breast cancer cell lines. Receptor activator of NF-κB ligand (RANKL), the ligand of RANK, plays a pivotal, lineage-specific role in tumorigenesis and/or metastasis. Binding to RANK, RANKL triggers a cascade of intracellular signaling events resulting in tumor metastasis. Recently, evidences demonstrated that RANKL inhibition could contribute to a better clinical outcome. Despite these encouraging data, the relationship between clinical outcome and tissue-based protein expression, especially RANK, is unclear. Women's health initiative (WHI) demonstrated that progestin increased the risk of several developing invasive cancers, including breast cancer and ovarian cancer. Dougall and Penninger demonstrated MPA could induce massive RANKL expression in the mammary gland via progestin receptor. RANKL, binding to RANK on mammary epithelial cells, promotes cell-cycle progression and protects these cells from apoptosis in response to DNA damage. These effects seem to be mediated by means of RANK/RANKL and IKK-α-NF-κB signaling.
Wang J, Liu Y, Wang L, Sun X, Wang Y. Clinical prognostic significance and pro-metastatic activity of RANK/RANKL via the AKT pathway in endometrial cancer. Oncotarget. 2016;7(5):5564-5575.