Pre-tumor exercise decreases breast cancer in old mice in a distance-dependent manner

Abstract

Epidemiological evidence supports a protective effect of physical activity for breast cancer but pre-clinical studies are needed to help define the underlying mechanisms in an age-related manner. We utilized 18-month old BALB/c mice injected in the mammary fat pad with syngeneic 4T1 tumor cells as a model of invasive breast cancer. A negative correlation was observed between daily distance ran, prior to tumor injection, and absolute tumor mass measured at necropsy (Pearson's r = -0.89, P = 0.0066, R(2) = 0.80). A correlation was also observed between distance ran before tumor implant and the histological score for mitotic index (Pearson's r = -0.85, P = 0.034, R(2) = 0.72). Runners showed an increased respiratory exchange ratio during the light cycle (P = 0.029) suggesting that voluntary running shifted resting substrate metabolism toward glucose oxidation, relative to lipid oxidation. The shift in substrate metabolism was significantly different from baseline for both groups of animals, indicating that the tumor burden might have been responsible. The observations from this study indicate that running longer distances is associated with decreased breast tumor burden in old mice, suggesting that physiological factors generated by exercising before tumor onset are protective against tumor progression. The mechanisms for this protective effect are not known but the data show that older mice are useful models to address specific questions in cancer research and support further studies on the ability of exercise training to protect older women at risk for breast cancer.

Keywords: Breast cancer; exercise; protective effect.

Figure 1

Singly housed, 18 months old BALB/c mice readily and consistently use slanted running wheels placed inside the cage in a tumor dependent manner. The mice were allowed to run 60 days before injection with 4T1 breast tumor cells, and an additional 30 days after tumor cell injection, at which time they were euthanized and tumors measured. A. Mice ran longer distances before tumor cell injection compared to after tumor cell injection, p = 0.0006. B. Mice that ran longer distances before tumor cell injection had decreased tumor mass measured at the time of euthanasia, Pearson’s r = -0.89, P = 0.0066, R² = 0.80. C. There was also a negative correlation between pre-tumor running distance and primary tumor mitotic index, Pearson’s r = -0.85, P = 0.034, R² = 0.72.

Figure 2

Voluntary wheel running induces a metabolic response in 18 months old BALB/c mice. The rates of oxygen consumption (VO₂; mL/kg/hour) and carbon dioxide production (VCO₂; mL/kg/hour) were measured at intervals of 20 minutes over 24 hours using the Oxymax system (Columbus Instruments, Columbus, OH). The respiratory exchange ratio (RER) was calculated from the ratio of VCO₂/VO₂. Assessments were conducted prior to group randomization (baseline) with 7 runners and 6 non-runners, and one week prior to euthanasia (final) with 8 runners and 8 non-runners. A. An increase in VO₂ during the active night cycle measured one week before euthanasia was positively correlated with increased running distance measured in mice before 4T1 tumor cell injection, Pearson’s r = 0.83, P = 0.041, R² = 0.69. B and C. The average RER increased in both runners (P = 0.001) and non-runners (P = 0.0024, respectively. D. The average RER measured during the inactive (daytime) cycle one week before euthanasia was significantly higher in runners compared to non-runners (P = 0.029).