Physical activity and nutrition alter cancer risk with possible mechanisms including effects on inflammation, insulin-like growth factors, insulin resistance, steroid hormones and lipid metabolism. A yet unexplored possible mechanism linking energy balance to cancer risk includes effects on DNA repair capacity. Defects in DNA repair function are clearly carcinogenic and intriguing preliminary evidence suggests that regular exercise results in an adaptive response of enhanced antioxidant defenses and DNA repair. DNA repair capacity also plays a central role in that inflammatory process can increase oxidative DNA damage. The proposed Project 4 of the Seattle TREC will address the intersection of diet, physical activity, weight, and body composition on biomarkers of cancer risk. The research will be ancillary to a funded human clinical trial of exercise and caloric restriction. Primary specific aims are to investigate the separate and combined effects of 1-year of exercise and/or a reduced-calorie diet among 503 postmenopausal women on 1) biomarkers of inflamation (C-reactive protien, serum amyloid A, interleukin-6), 2) DNA damage sensitivity and DNA repair capacity, and 3) plasma protien patterns (proteomics) Investigations of intervention effects on plasma protien patterns will enable us to identify possible new mechanisms linking exercise or a reducedcalorie diet to carcinogenesis. As secondary outcomes we will evaluate intervention effects on gene expression of DNA repair genes and on biomarkers of obesity. Further, we will investigate whether intervention effects differ by body mass index or body composition prior to the intervention or or dependent on changes in body composition during the course of interventions. Finally, we will explore wether genetic characteristics modify the intervention effects. The proposed measurements will be complemented by biomarkers already planned within the funded parent grant (Insulin, IGF1, IGFBP3, steroid hormones) and allow for investigations of interactions with the newly investigated pathways. Thus, Project 4 provides a comprehensive and cost-effective approach for investigating the independent and combined effects of exercise and caloric restriction on biomarkers of cancer risk among humans. Close collaborations with Projects 2, 3, and 5 will enhance our understanding of the mechanistic effects linking exercise and energy balance to cancer risk.
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