Abstract 905: Investigating the effects of aerobic exercise on preclinical breast cancer outcomes
Authors: Wakefield Zachary Richard , Tanaka Mai , Bundy Angela , Lepler Sharon , Pampo Christine , Rice Lori , Siemann Dietmar W. 
Published: July 2021

Abstract
Aerobic exercise is receiving increased recognition in oncology spheres for its multiple purported benefits. Exercise is known to induce physiologic responses that improve patient quality-of-life parameters as well as all-cause mortality. There is also a growing body of evidence that suggests exercise may directly impact tumor biology and therapy outcomes. Previous studies suggest that exercise can improve tumor perfusion and ameliorate intratumoral hypoxia, increase recruitment of cytotoxic immune cells, and alter metabolic substrate availability. Furthermore, the physiologic adaptations to exercise in normal tissue may protect against treatment-associated toxicity and allow for greater treatment tolerance. With regard to cancer metastasis, reports have been conflicting. The goal of this study was to characterize the effect of exercise on normal tissue adaptations, tumor microenvironment, metastasis, and doxorubicin cardiotoxicity in preclinical breast cancer models. Female, retired breeder BALB/c mice were employed, and aerobic exercise was modeled by singly-housing mice with access to wireless, low-profile voluntary running wheels. Sedentary controls were singly housed with plastic huts. Syngeneic 4T1 or EMT6 breast adenocarcinoma cells were inoculated either intraductally into the 4th mammary duct or intravenously into the tail-vein. In one study, doxorubicin was administered via 3 intraperitoneal (IP) injections over 7 days for a total dose of 11 mg/kg. Exercising mice steadily increased the amount they ran until they reached a plateau of 10-12 km/day from day 10 onward. This exercise regime induced cardiac hypertrophy and oxidative phenotypes in the quadriceps muscle relative to non-wheel running controls. It also prevented the cardiac atrophy and bodyweight loss induced by doxorubicin treatment. In mice bearing intraductal EMT6 tumors, exercise delayed tumor growth and improved survival relative to non-wheel running controls. However, exercise did not alter 4T1 tumor growth or survival. The effect of exercise on metastasis was assessed under three conditions, 1) in mice that ran before and after intravenous 4T1 cell injection, 2) mice that had limited (low exercise) or full (high exercise) access to running wheels after intravenous 4T1 cell injection, and 3) mice than ran after intraductal 4T1 cell injection. Under all three conditions, exercise did not affect the establishment of pulmonary macro-metastases. Taken together, these data suggest that while aerobic exercise may impact tumor growth and metastasis only in some tumor models, the normal tissue adaptations induced by exercise can be sufficient to protect against chemotherapy toxicity, thus warranting further studies of this modality in oncology settings.
Citation Format: Zachary Richard Wakefield, Mai Tanaka, Angela Bundy, Sharon Lepler, Christine Pampo, Lori Rice, Dietmar W. Siemann. Investigating the effects of aerobic exercise on preclinical breast cancer outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 905.