Role of Oncostatin M in Exercise-Induced Breast Cancer Prevention

Abstract

Moderate-to-vigorous-intensity physical activity decreases the risk of breast cancer. The muscle-derived cytokine (myokine), oncostatin M (OSM), has been shown to decrease breast cancer cell proliferation. We hypothesized that OSM is involved in physical activity-induced breast cancer prevention, and that OSM antibody (Anti-OSM) administration would mitigate the effect of physical activity in a rat model of mammary carcinoma. Female Sprague Dawley rats were injected with 50 mg/kg N-methyl-N-nitrosourea to induce mammary carcinogenesis. During the 20-week study, rats were exercise trained (EX) or remained sedentary (SED). Additional groups were treated with Anti-OSM antibody (SED + Anti-OSM and EX + Anti-OSM) to explore the impact of OSM blockade on tumor latency. Exercise training consisted of treadmill acclimation and progressive increases in session duration, speed, and grade, until reaching 30 min/day, 20 m/min at 15% incline. Experimentally naïve, age-matched, female rats also completed an acute exercise test (AET) with time course blood draws to evaluate OSM plasma concentrations. Relative tumor-free survival time was significantly longer in EX animals (1.36 ± 0.39) compared to SED animals (1.00 ± 0.17; p = 0.009), SED + Anti-OSM animals (0.90 ± 0.23; p = 0.019), and EX + Anti-OSM animals (0.93 ± 0.74; p = 0.004). There were no significant differences in relative tumor latency between SED, SED + Anti-OSM, or EX + Anti-OSM animals. Following the AET, OSM plasma levels trended higher compared to baseline OSM levels (p = 0.080). In conclusion, we observed that exercise-induced delay of mammary tumor development was mitigated through Anti-OSM administration. Thus, future studies of the OSM mechanism are required to lay the groundwork for developing novel chemo-prevention strategies in women who are unable or unwilling to exercise.

Keywords: animal model; breast cancer prevention; motorized treadmill; myokine; n-methyl-n-nitrosourea; oncostatin M.

Figure 1

Schematic of the experimental timeline. All rats were acclimated to the treadmill prior to randomization into experimental groups. After treadmill ramp up, exercised rats continued training 5 days per week for the duration of this study (week 3–20). MNU = n-methyl-n-nitrosourea. Anti-OSM = Mouse anti-oncostatin M.

Figure 2

(A) Rat body weight growth curve over 20 weeks. Week 0 = pre-MNU injection weight. All SED + Anti-OSM rats were euthanized by week 14 due to tumor burden reaching 4 cm³. The drop in average SED weights during weeks 19 and 20 was due to a decrease in animal numbers from tumor burden reaching 4 cm³ (SED n = 2 at week 19). No statistical significance. (B) Average heart weight to carcass weight ratio. SED n = 15, EX n = 14, SED + Anti-OSM n = 5, EX + Anti-OSM n = 12. No statistical significance. x = group mean.

Figure 3

Representative photos of malignant tumors from each group. (A) SED. (B) EX. (C) SED + Anti-OSM. (D) EX + Anti-OSM. All scale bars represent 1 cm.

Figure 4

Average normalized tumor latency across groups (SED n = 14, EX n = 14, SED + Anti-OSM n = 5, EX + Anti-OSM n = 10). * p < 0.05, † p < 0.01. x = group mean.

Figure 5

Plasma OSM concentrations after 1 h of exercise on motorized treadmill. OSM was measured from plasma samples isolated from blood collected at three different timepoints (before, immediately after, and 2 h after) from experimentally naïve rats (n = 7). **: p = 0.080.