Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel running showed over 60% reduction in tumor incidence and growth across five different tumor models. Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed that NK cells were mobilized by epinephrine, and blockade of β-adrenergic signaling blunted training-dependent tumor inhibition. Moreover, epinephrine induced a selective mobilization of IL-6-sensitive NK cells, and IL-6-blocking antibodies blunted training-induced tumor suppression, intratumoral NK cell infiltration, and NK cell activation. Together, these results link exercise, epinephrine, and IL-6 to NK cell mobilization and redistribution, and ultimately to control of tumor growth.

Cumulative epidemiological evidence shows that regular exercise lowers the risk of developing breast cancer and decreases the risk of disease recurrence. The causality underlying this relation has not been fully established, and the exercise recommendations for breast cancer patients follow the general physical activity guidelines, prescribing 150 min of exercise per week. Thus, elucidations of the causal mechanisms are important to prescribe and implement the most optimal training regimen in breast cancer prevention and treatment. The prevailing hypothesis on the positive association within exercise oncology has focused on lowering of the basal systemic levels of cancer risk factors with exercise training. However, another rather overlooked systemic exercise response is the marked acute increases in several potential anti-cancer components during each acute exercise bout. Here, we review the evidence of the exercise-mediated changes in systemic components with the ability to influence breast cancer progression. In the first part, we focus on systemic risk factors for breast cancer, i.e., sex hormones, insulin, and inflammatory markers, and their adaptation to long-term training. In the second part, we describe the systemic factors induced acutely during exercise, including catecholamines and myokines. In conclusion, we propose that the transient increases in exercise factors during acute exercise appear to be mediating the positive effect of regular exercise on breast cancer progression.