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

AMERICAN JOURNAL OF CANCER RESEARCH44378-38

Exercise training in transgenic mice is associated with attenuation of early breast cancer growth in a dose-dependent manner.

Epidemiological research suggests that regular physical activity confers beneficial effects that mediate an anti-tumor response and may reduce cancer recurrence. It is unclear what amount of physical activity is necessary to exert such a protective effect and what mechanisms are involved. We investigated the effects of voluntary wheel running on tumor progression and cytokine gene expression in the transgenic polyoma middle T oncoprotein (PyMT) mouse model of invasive breast cancer. Runners showed significantly reduced tumor sizes compared with non-runners after 3 weeks of running (p ≤ 0.01), and the greater the running distance the smaller the tumor size (Pearson's r = -0.61, p ≤ 0.04, R(2) = 0.38). Mice running greater than 150 km per week had a significantly attenuated tumor size compared with non-runners (p ≤ 0.05). Adipose tissue mass was inversely correlated with tumor size in runners (Pearson's r = -0.77, p = 0.014) but not non-runners. Gene expression of CCL22, a cytokine associated with recruitment of immunosuppressive T regulatory cells, was decreased in tumors of runners compared to non-runners (p ≤ 0.005). No differences in tumor burden or metastatic burden were observed between runners and non-runners after ten weeks of running when the study was completed. We conclude that voluntary wheel running in PyMT mice correlates with an attenuation in tumor progression early during the course of invasive breast cancer. This effect is absent in the later stages of overwhelming tumor burden even though cytokine signaling for immunosuppressive regulatory T cells was down regulated. These observations suggest that the initiation of moderate exercise training for adjunctive therapeutic benefit early in the course of invasive breast cancer should be considered for further investigation

Gene expression of CCL22 but not CXCR4 is attenuated in tumors from runners but not non-runners.

<p><b>A</b>. Tumors from runners showed four fold decrease in CCL22 (p = 0.0046, N = 4 per condition). <b>B</b>. Tumors from runners had increased expression of CXCR4 (p = 0.04, N = 3 per condition).</p

Runners with increased fat mass had decreased tumor burden.

<p><b>A</b>. The amount of adiposity at sacrifice was significantly correlated with tumor burden in runners (Pearson's r = −0.77, p = 0.01, R² = 0.6). <b>B</b>. Both runners and non-runners showed a time-dependent fat loss, and <b>C</b>. increased lean mass. <b>D</b>. Runners had increased heart weights compared to non-runners.</p

The surface area of breast tumors in PyMT transgenic mice was decreased after three weeks of voluntary wheel running.

<p>Values are means ± standard deviation (N = 12 per group). A. Size of all breast tumors in runners was significantly decreased compared to non-runners (p = 0.01). B. Differences in tumor sizes were observed across the anterior (1–3) and posterior (4–5) mammary glands (p = 0.04). C. Runners have a significant decrease in tumor size in mammary gland 1 after 5 weeks of running (p = 0.03). D. Runners showed a biphasic pattern in the weekly distance ran (km). Tumor growth showed a weekly increase.</p

Spleen weights obtained at sacrifice in transgenic (N = 7 runners and 8 non-runners) and wild-type mice (N = 3 per condition) were increased in transgenic non-runners compared with wild-type runners (p = 0.03), but no other significant differences were observed.

<p>Spleen weights obtained at sacrifice in transgenic (N = 7 runners and 8 non-runners) and wild-type mice (N = 3 per condition) were increased in transgenic non-runners compared with wild-type runners (p = 0.03), but no other significant differences were observed.</p

The number and size of breast tumors in PyMT mice correlated with distance run.

<p><b>A</b>. Distance run at 3 weeks was associated with the number of palpable tumors during the 3rd week (Pearson's r = −0.6, p = 0.051, R² = 0.36), <b>B</b>, total tumor sizes (Pearson's r = −0.6, p = 0.0504, R² = 0.36), and <b>C</b>, anterior tumor sizes (glands 1–3) (Pearson's r = − 0.61, p = 0.044, R² = 0.38). <b>D</b>. High volume runners demonstrated significantly smaller tumor sizes compared with non-runners during the 3rd week (p<0.05), but not with low volume runners. <b>E</b>. Distance ran at 3 weeks was correlated with total tumor size in runners during the 5th week (Pearson's r = −0.65, p = 0.023, R² = 0.42). <b>F</b>. Distance run at 4 weeks was correlated with total tumor size in runners during the 5th week (Pearson's r = −0.57, p = 0.054, R² = 0.32).</p