RANK as a therapeutic target in cancer

The RANK signaling pathway has emerged as a new target in breast cancer as receptor activator of nuclear factor κB ligand (RANKL) and its receptor RANK mediate the pro-tumorigenic role of progesterone in the mammary gland. Thousands of cancer patients worldwide are already taking RANKL inhibitors for the management of bone metastasis, given the relevance of this pathway in osteoclastogenesis and bone resorption. RANK signaling also has multiple divergent effects in immunity and inflammation, both in the generation of active immune responses and in the induction of tolerance: it is required for lymph node organogenesis, thymic medullary epithelial development and self-tolerance, and regulates activation of several immune cells and inflammatory processes. The RANK pathway interferes with mammary epithelial differentiation and mediates the major proliferative response of mammary epithelium to progesterone and progesterone-driven expansion of mammary stem cells; it also controls hair follicle and epidermal stem cell homeostasis, pointing to RANK as a key regulator of epithelial stemness. Here we revisit the main functions of RANK signaling in bone remodeling, immune cells and epithelial differentiation. We also discuss the mechanistic evidence that supports its pleiotropic effects on cancer: from bone metastasis to immune and cancer-cell-dependent effects.