RANKL may regulate spontaneous mammary tumor formation and metastasis driven by the potent oncogene Neu. RANKL blockade effectively attenuated the formation of mammary tumors and pulmonary metastasis in the MMTV-Neu transgenic mouse model. Interestingly, OPG may serve as a positive regulator of microvessel formation and may promote neovascularization that is important for tumor progression. OPG overexpression by breast cancer cells enhances orthotopic and osseous tumor growth. In light of all these findings, AP24534RANKL/RANK/OPG signaling pathway has emerged as a promising therapeutic target of cancer. Denosumab, a monoclonal antibody against RANKL, has been approved for the treatment of postmenopausal osteoporosis and bone metastasis in breast cancer. OPG was initially derived from an expressed sequence tag of a fetal rat intestine cDNA library encoding a 401-amino-acid polypeptide. Subsequently, a physiological role of OPG in the maintenance of normal bone mass was underscored by several studies. The later finding in murine myelomonocytic cell line 32D led to the identification of OPG binding protein or OPGL, which has identical sequence as RANKL and was further implicated with the osteoclast development. Direct sequencing of a human bone marrow-derived myeloid dendritic cell cDNA library identified RANK as a novel TNFR homologue. Subsequently,Axitinib RANKL was identified from murine thymoma cell line EL40.5 as well as in T cells. RANKL exists as a homotrimer and induces receptor clustering upon engaging RANK on the cell surface, consequently causes receptor clustering. Activation events within the cell are initiated through TNFR-associated factors following sufficient RANK clustering. Genetic variants in the OPG locus have previously been implicated with osteoporotic fracture, bone turnover, bone mineral density, osteonecrosis, diabetic neuroarthropathy as well as ankylosing spondylitis. Alterations at the RANK locus and/or functionally related genes, such as RANKL, have also been reported to be associated with rheumatoid arthritis, aortic calcification, bone mineral density and Paget’s disease of bone.