The role of osteoblastic β-adrenergic signaling in breast cancer metastasis to bone

Abstract

Metastases are the primary cause of death in breast cancer patients, most often appearing in the bones. Following treatment of the primary cancer, emotional and psychosocial factors within this population hasten time to recurrence and death, however the underlying mechanism(s) remain unclear. Using two mouse models of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes breast cancer metastasis and progression in the skeleton. Adrenergic signaling in the bone stroma increases cancer cell colonization of bone and accelerates osteolytic bone disease at later stages. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following β2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. In addition to increasing the likelihood of metastasis, we also demonstrate that β2AR signaling can accelerate bone destruction in cancer induced bone disease via osteoblastic RANKL. The emerging clinical implication, supported by recent epidemiological studies, is that βAR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the “vicious cycle” of bone destruction induced by these cells.