Bone Microenvironment and Role of Rank-Rankl-Opg in Breast Cancer Metastasis in Bone

Abstract

Bone metastasis affects more than 70% of advanced breast cancer patients and is the leading cause of breast cancer-related deaths, incapable of being controlled, still very unpredictable. As a consequence, this has led to increased mortality and worsen quality of life in these patients by causing severe complications such as excruciating bone pain, hypercalcemia and spinal cord compression, pathological fractures also known as skeletal related events (SRE). Vast majority of breast cancer patients with relapses in bone are asymptomatic during the course of the disease, hence making it difficult to diagnosis and detect the spread of the breast cancer cells to the bone prior to appearance of bone pain complains issued by this category of patients.   Due to increased frequency of bone metastases in breast cancer during the recent years, understanding cross-communications between tumor cells and bone cells accompanied by the action of various growth factors, proinvasive cytokines, chemokines released upon bone destruction are essential to help improve the development of new effective therapeutic interventions. The pathogenesis of bone metastases in breast cancer depends on the bidirectional tight interaction among breast cancer cells and various stromal cells also being identified as the “vicious cycle”, which modulates the bone niche resulting in continuous activation of bone resorption process. One of the major important pathways involved in the development and progression of bone metastases in breast cancer is RANK-RANKL-OPG cascade, where a positive shift towards RANKL-RANK axis favors proliferation, activation and survival of osteoclasts, thus promoting tumorigenesis and metastasis in the bone. In this context, disturbance of RANKL-RANK interplay should be an effective method to prevent the survival and growth of the breast cancer cell in the bone microenvironment.