Although multidisciplinary therapeutic strategy has been recommended, the prognosis is still poor. Tobacco use, alcohol consumption, low socioeconomic status, poor oral hygiene and nutritional deficiencies have been identified as risk factors for esophageal cancer. Yet, only a subset of individuals exposed to these risk factors eventually develop esophageal cancer,AZ 960 indicating a pivotal role of genetic factors, such as single nucleotide polymorphisms, in the esophageal carcinogenesis. Recently, the osteoprotegerin, its binding protein–the receptor activator of NF-kB and RANK ligand have been implicated with the pathogenesis of breast cancer. OPG was initially identified from a fetal rat intestine cDNA library, which is unique for it only exists as a secreted molecule in contrast to the other membrane-bound cell surface members of tumor necrosis factor receptor family. RANKL is the OPG binding protein, AZD2281 while RANK constitutes the cell surface receptor which responses to OPGL. In numerous rodent models of tumor, RANKL signal is increased through diverse mechanisms. OPG neutralizes RANKL, which leads to a reduced RANKL-RANK interaction. RANKL expression was verified in various tumor types and inflammatory cells associated with tumor. Elevation in stromal RANKL has been detected at local sites of bone metastasis or multiple myeloma, causing enhanced osteoclast activity and bone destruction. In experimental models, RANKL inhibitors reduced tumor-induced osteolysis in various types of cancer, reduced bone destruction, skeletal tumor progression, as well as tumor burden. In addition, RANKL-RANK pathway may contribute to the primary tumorigenesis and metastasis independently of its effects on tumor-related osteolysis. Regulated by factors including prolactin and progesterone, RANKL could drive the primary mitogenic response of mammary epithelium and the expansion of mammary stem cells via RANK activation, which may therefore induce mammary cancer by offering a more transformation-susceptible target pool.