Purpose: Exercise decreases breast cancer risk and disease recurrence, but the underlying mechanisms are unknown. Training adaptations in systemic factors have been suggested as mediating causes. We aimed to examine if systemic adaptations to training over time, or acute exercise responses, in breast cancer survivors could regulate breast cancer cell viability in vitro.

Methods: Blood samples were collected from breast cancer survivors, partaking in either a 6-month training intervention or across a 2 h acute exercise session. Changes in training parameters and systemic factors were evaluated and pre/post exercise-conditioned sera from both studies were used to stimulate breast cancer cell lines (MCF-7, MDA-MB-231) in vitro.

Results: Six months of training increased VO2peak (16.4 %, p < 0.001) and muscle strength, and reduced resting levels of plasma cholesterol (−18.2 %, p = 0.003) and cytokines. Yet, these systemic adaptations had no effect on breast cancer cell viability in vitro. During 2 h of acute exercise, increases in serum lactate (6-fold, p < 0.001), epinephrine (2.9-fold, p = 0.009), norepinephrine (2.2-fold, p < 0.001), and cytokines, including IL-6 (2.1-fold, p < 0.001) were detected. Incubation with serum obtained after exercise reduced viability by −9.2 % in MCF-7 (p = 0.04) and −9.4 % in MDA-MB-231 (p < 0.001) compared to resting serum.

Conclusion: Systemic changes to a 2 h exercise session reduced breast cancer viability, while adaptations to 6 months of training had no impact. Our data question the prevailing dogma that training-dependent baseline reductions in risk factors mediate the protective effect of exercise on breast cancer. Instead, we propose that the cancer protection is driven by accumulative effects of repeated acute exercise responses.