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Obesity-associated breast cancer recurrence is mechanistically linked with elevated insulin levels and insulin resistance. Exercise and weight loss are associated with decreased breast cancer recurrence, which may be mediated through reduced insulin levels and improved insulin sensitivity. This is a secondary analysis of the WISER Survivor clinical trial examining the relative effect of exercise, weight loss and combined exercise and weight loss interventions on insulin and insulin resistance. The weight loss and combined intervention groups showed significant reductions in levels of: insulin, C-peptide, homeostatic model assessment 2 (HOMA2) insulin resistance (IR), and HOMA2 beta-cell function (β) compared to the control group. Independent of intervention group, weight loss of ≥10% was associated with decreased levels of insulin, C-peptide, and HOMA2-IR compared to 0-5% weight loss. Further, the combination of exercise and weight loss was particularly important for breast cancer survivors with clinically abnormal levels of C-peptide.

Simple Summary: Exercise is well known to decrease the risk of breast cancer. The cellular processes that contribute to exercise-induced cancer prevention are less known. We conducted an exercise training study in rats given a chemical to induce breast cancer. Exercise increased the length of time to development of breast cancer in rats. However, when we gave the rats an antibody which binds to a certain cellular protein (oncostatin M), exercise-induced protection against breast cancer was not observed. These observations may be useful in future studies as the oncostatin M protein is produced by muscles. Thus, these results support a link between muscle use during exercise and breast cancer prevention. Future studies may examine oncostatin M and other proteins produced by exercising muscles for their potential role in breast cancer prevention. 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. [ABSTRACT FROM AUTHOR]

Purpose: Physical inactivity and obesity increase risk for breast cancer recurrence and cardiovascular death; inflammation is hypothesized to mediate these associations. Methods: In a four-arm randomized controlled trial, 318 breast cancer survivors with overweight or obesity were randomized to exercise alone, weight loss alone, exercise plus weight loss, or control for 12 months. Inflammation outcomes included C-reactive protein (CRP), serum amyloid A (SAA), intracellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). Results: Compared with control, exercise alone increased ICAM-1 (9.3%; 95% confidence interval [CI] = 1.6–16.9) and VCAM-1 (8.6%; 95% CI = 2.6–14.5) but did not change CRP or SAA. Compared with control, weight loss alone reduced CRP (−35.2%; 95% CI = −49.9 to −20.7), and SAA (−25.6%; 95% CI = −39.8 to −11.9) but did not change ICAM-1 or VCAM-1. Compared with control, exercise plus weight loss reduced CRP (−44.1%; 95% CI = −57.1 to −31.1) and SAA (−26.6%; 95% CI = −40.5 to −12.6) but did not change ICAM-1 or VCAM-1. Among 194 participants with elevated CRP at baseline (e.g., >3 mg·L−1), compared with control, weight loss alone (0.17; 95% CI = 0.04–0.30) and exercise plus weight loss (0.31; 95% CI = 0.16–0.46) increased the probability of achieving normal CRP at month 12. In analyses that consolidated randomized groups, body weight and adiposity reductions, but not change in fitness level, correlated with decreased CRP, SAA, and ICAM-1 levels. Conclusions: In breast cancer survivors with overweight or obesity, weight loss or exercise plus weight loss reduced measures of inflammation that are associated with breast cancer recurrence and cardiovascular death. [ABSTRACT FROM AUTHOR]

Chronically elevated levels of inflammatory biomarkers may contribute to the development of cancer and diet may be an important factor in the interplay between inflammation and cancer. We examined associations between glycemic load (GL), glycemic index (GI), and adapted dietary inflammatory index (ADII) and markers of inflammation and adipokines in 135 premenopausal women at high genetic risk for breast cancer (NCT00892515). We assessed body mass index (BMI), 3-day food records, and blood biomarkers TNF-α, IL-12, CCL2, IL-10, leptin, and adiponectin. Regression models assessed associations between dietary variables and biomarkers, adjusted for caloric intake and BMI. Participants were on average 34.2 years old with mean BMI of 26.8 kg/m2. Significantly higher levels of IL-10 and leptin were observed in participants with higher GI. Leptin and adiponectin were significantly associated with ADII. Leptin remained associated with ADII after adjustment for caloric intake and BMI. There were no associations between inflammatory biomarkers of interest and GL, GI, and ADII, after adjusting for caloric intake and BMI. Elevated leptin levels were observed with higher ADII independent of caloric intake and BMI. The relationship between carbohydrate quality and inflammatory potential of the diet and markers of inflammation may be modulated by leptin. [ABSTRACT FROM AUTHOR]

Background: Increased levels of inflammation are associated with many diseases, including cancer. Physical activity can lower breast cancer risk as well as levels of inflammation. The Women In Steady Exercise Research (WISER) Sister trial was a randomized controlled trial that investigated the effects of a dosed, moderate to vigorous, aerobic exercise intervention on levels of inflammation in premenopausal women who were at high risk of developing breast cancer.Methods: Participants were randomized to control (<75 minutes per week; 41 patients), low-dose exercise (150 minutes per week; 38 patients), or high-dose exercise (300 minutes per week; 37 patients) groups. The 5-menstrual cycles-long, home-based treadmill exercise intervention gradually increased in minutes per week and intensity up to a maximum of 80% of the age-predicted maximum heart rate. Blood was collected at baseline and at follow-up and assayed for chemokine (C-C motif) ligand 2 (CCL2), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor α (TNF-α).Results: A linear dose-response relationship was observed for the proinflammatory biomarkers CCL2 (%Δ of -5.44% in the control group, -0.03% in the low-dose exercise group, and 1.54% in the high-dose exercise group), IL-12 (%Δ of -21.5% in the control group, 38.2% in the low-dose exercise group, and 25.8% in the high-dose exercise group,) and TNF-α (%Δ of -4.69% in the control group, 9.51% in the low-dose exercise group, and 15.7% in the high-dose exercise group) but not for the anti-inflammatory biomarker IL-10 (%Δ of 5.05% in the control group, 6.05% in the low-dose exercise group, and 10.6% in the high-dose exercise group). For IL-12 and TNF-α, the percentage change was significantly higher in the low-dose (IL-12: P < .001; and TNF-α: P = .01) and high-dose (IL-12: P < .001; and TNF-α: P < .001) exercise groups compared with the control group.Conclusions: Moderate to vigorous aerobic exercise appeared to increase levels of proinflammatory biomarkers in a dose-dependent manner in a population of healthy women at high risk of developing breast cancer. The results of the current study suggest that for healthy premenopausal women, the mechanism of reduced breast cancer risk observed in physically active individuals may not be a result of reduced levels of inflammation. [ABSTRACT FROM AUTHOR]