Androgen Signaling in Metastatic Bone Disease

Bone metastases are the major cause of morbidity and mortality from solid tumors. In general, the rate of bone metastases from solid tumors is 30%–40%. However, this rate is much higher in prostate cancer (PCa), approaching 90% in patients with advanced disease. Androgens and androgen receptor (AR) signaling plays a seminal role in PCa at all stages in the multistep process of bone metastases, affecting both the seed (PCa) and the soil (bone). AR signaling in prostate cancer cells promotes growth at the primary site, invasion, angiogenesis, epithelial to mesenchymal transition and bone targeting. Androgen deprivation therapy (ADT) enhances osteolysis and potentially promotes PCa entry into bone. In established osteoblastic bone metastases, androgens promote Wnt signaling in osteoblasts and the secretion of factors that further promote PCa growth in bone. The AR signaling pathway continues to promote the growth of castration resistant PCa (CRPC). Mechanisms of castration resistance include upregulation of androgen synthesis in PCa cells, AR overexpression, AR mutations and increased expression of AR variants. Novel therapeutics targeting the androgen signaling pathway in combination with traditional ADT have shown efficacy in delaying onset and progression of bone metastases.