Abstract 2965: Aerobic exercise delays intraductal breast cancer growth and suppresses doxorubicin-induced skeletal and cardiac muscle toxicities

Aerobic exercise enacts physiologic adaptations across multiple tissue types that have positive effects on health and well-being in a number of chronic diseases. In cancer patients, exercise can improve quality of life by improving mood, reducing fatigue, and increasing therapy tolerance. Preclinical evidence suggests that exercise may also have direct effects on the tumor, such as improving perfusion, limiting hypoxia, and increasing immune cell infiltration. Furthermore, physiologic adaptations to exercise may protect against treatment toxicities. The goal of this project was to analyze the effect of aerobic exercise on breast cancer growth and doxorubicin-induced toxicity in a preclinical setting. These studies utilized retired breeder, female BALB/c mice. Aerobic exercise was modeled by singly-housing mice in cages with access to wireless, low-profile voluntary wheel running. Sedentary controls were singly-housed with plastic huts. To assess the impact of exercise on tumor growth, mice were intraductally injected with murine EMT6 breast cancer cells (103 cells in 5 µL) and then randomized into sedentary or exercising groups. Tumor volume was measured, and endpoint was defined as tumor volume of 1200 mm3. To examine the effect of exercise on doxorubicin-induced toxicity, non-tumor bearing mice were randomized into sedentary or exercising groups and given 3 intraperitoneal injections of doxorubicin (total dose 11 mg/kg) on days 10, 13, and 16 after randomization. The experiment was terminated on day 21. In both studies, mice were euthanized at endpoint and tissues were harvested, weighed, and either snap-frozen, or OCT- or paraffin-embedded. The results showed that aerobic exercise delayed tumor growth and improved survival in the intraductal EMT6 model. Proteomic profiling with a cytokine array revealed differential expression of Reg3G, MMP-9, and Tissue Factor between sedentary and exercising tumors. Moreover, chemotherapy treatment trended to decrease skeletal and cardiac muscle masses relative to untreated controls, and exercise prevented these effects. Doxorubicin also induced differential cardiac gene expression of α-MHC, β-MHC, and SERCA 2a relative to untreated controls, and exercise prevented these effects in 2 of 3 markers. In conclusion, aerobic exercise delayed tumor growth and improved survival in an intraductal model of breast cancer. Exercise also suppressed doxorubicin-induced skeletal and cardiac muscle toxicities. These findings suggest that aerobic exercise may have the potential to improve therapy outcomes by affecting both tumor growth and chemotherapy toxicities when implemented during treatment. Citation Format: Zachary Wakefield, Angela Bundy, Sharon Lepler, Christine Pampo, Lori Rice, Dietmar Siemann. Aerobic exercise delays intraductal breast cancer growth and suppresses doxorubicin-induced skeletal and cardiac muscle toxicities [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2965.