Bone and lung metastases are responsible for the majority of deaths in patients 
with breast cancer. Following treatment of the primary cancer, emotional and 
psychosocial factors within this population precipitate time to recurrence and 
death, however the underlying mechanism(s) remain unclear. Using a mouse model 
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 MDA-231 breast cancer cell 
colonization of bone via a neurohormonal effect on the host bone marrow stroma. 
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. 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.