PROJECT SUMMARY/ABSTRACT Targeting chronic inflammation related to obesity with exercise has the potential to improve prognosis in obese postmenopausal breast cancer survivors. Obesity is considered a leading modifiable contributor to breast cancer mortality worldwide due to its association with increased recurrence and decreased overall survival rate. A central mechanism by which obesity stimulates cancer progression is through chronic, low-grade inflammation in adipose tissue. In particular, white adipose tissue (WAT) is a metabolically complex organ comprised of adipocytes capable of secreting adipokines and proinflammatory cytokines related to tumorigenesis. Chronic inflammation of WAT includes accumulation of adipose tissue macrophages (ATMs). Specifically, the ATM M1 phenotype, elevated with obesity, provides a rich source of cytokines, which are key mediators of obesity-associated insulin resistance. Gains in fat mass and a decline in lean mass, known as sarcopenic obesity, are observed as a treatment side effect, further contributing to the development of WAT and subsequent elevated M1 expression. Favorably, exercise- induced changes in sarcopenic obesity lead to a reduction in M1 ATMs, and increase in M2 ATMs known to protect against insulin resistance by attenuating inflammation. However, it is unknown what impact this may have on cancer prognosis and what forms of exercise are most effective at reducing chronic inflammation. Our general hypothesis is that exercise designed to target chronic inflammation and associated sarcopenic obesity will improve prognosis in obese postmenopausal breast cancer survivors. We propose a Phase II RCT to compare the effects of two combined aerobic and resistance exercise interventions relative to an attention control group among early-stage obese postmenopausal breast cancer survivors who have completed primary cancer therapy. This proposal will address the following aims: to determine the effects of exercise on 1) obesity-associated chronic inflammation and 2) sarcopenic obesity. This study is innovative because a) we will target adipose tissue inflammatory biomarkers to improve cancer prognosis, b) utilize a novel biopsy method to obtain deep subcutaneous abdominal adipose tissue to address a mechanistic prognostic question, and c) employ a unique periodized, circuit-style exercise design to reduce chronic inflammation. If the aims are achieved, findings from this study will generate new knowledge about exercise guidelines for breast cancer survivors most likely to improve prognosis.

PROJECT NARRATIVE Targeting chronic inflammation related to obesity with exercise has the potential to improve prognosis and comorbidities related to heart disease and diabetes in obese postmenopausal breast cancer survivors. Our proposal seeks to determine appropriate exercise regimens to reduce chronic inflammation that can be set forth as specific exercise guidelines to improve cancer prognosis.