Role of RANKL/RANK in primary and secondary breast cancer.

Bone is one of the most preferential metastatic target sites of breast cancer. Bone possesses unique biological microenvironments in which various growth factors are stored and continuously released through osteoclastic bone resorption, providing fertile soil for circulating breast cancer cells. Bone-disseminated breast cancer cells in turn produce osteotropic cytokines which modulate bone environments. Under the influences of breast cancer-produced cytokines, osteoblasts express elevated levels of Ligand for receptor activator of nuclear factor-κB (RANKL) and stimulate osteoclastogenesis via binding to the receptor receptor activator of nuclear factor-κB (RANK) and activating its downstream signaling pathways in hematopoietic osteoclast precursors, which causes further osteoclastic bone destruction. Establishment of crosstalk with bone microenvironments (so called vicious cycle) is an essential event for metastatic breast cancer cells to develop bone metastasis. RANKL and RANK play a central role in this crosstalk. Moreover, recent studies have demonstrated that RANKL and RANK are involved in tumorigenesis and distant metastasis independent of bone microenvironments. Pharmacological disruption of the RANKL/RANK interplay should be an effective therapeutic intervention for primary breast tumors and bone and non-bone metastasis. In this context, denosumab, which is neutralizing monoclonal antibody against RANKL, is a mechanism-based drug for the treatment of bone metastases and would be beneficial for breast cancer patients with bone metastases and potentially visceral organ metastases.