RANK or RANKL or OPG: The Axis of Breast Cancer Bone Metastasis Evil? - Abstract
Breast cancer bone metastasis remains the leading cause of death in individuals with advanced breast cancer of patients presenting with metastasis, ~ 70% is osseous. Generally, breast cancer bone metastasis is osteolytic, resulting in breakdown of the bone matrix. Treatment options are limited, and once breast cancer has metastasized to bone, it is incurable. The RANK/RANKL/OPG triad plays a critical role in breast cancer bone metastasis. Not only do the interactions of this triad facilitate and regulate normal bone turnover, it is also central to many signaling pathways in the metastatic bone microenvironment. Radiating from the RANK/RANKL/OPG axis, like spokes in a wheel, are factors such as TGF-beta, PTHrP, M-CSF, CCN2 and other cellular signaling pathways involved in the progression of breast cancer bone metastasis. Crosstalk between breast cancer cells and the bone microenvironment results in a vicious cycle of metastatic tumor promotion, progression and osteolysis. Furthermore, mounting evidence suggests that the RANK/RANKL/OPG axis also plays an important role in the development of breast carcinogenesis. However, the relationship between their differential expression in normal mammary epithelium and breast tumors is understudied and conflicting data from the literature muddies the role of each player in this triad in progression towards breast cancer bone metastasis. Thus, this review discusses the current status of RANK/RANKL/OPG expression and their involvement in breast cancer progression and metastasis and highlights the need to further understand the role of the triad.