Project Summary: Disturbances in the insulin- insulin-like grovirth factor (IGF) axis, levels of sex hormones, and adipocytokines have been implicated in pathways connecting obesity with the development of several major cancers. However, few studies have sought to determine the origins of variation in these cancer-related biomakers, which may be due to complex interrelationships between energetic factors such as diet, physical activity, and sleep patterns. Energetic factors may also be impacted by macro-level factors such as neighborhood social economical status (SES) and built environment. Finally, these relationships may be moderated by genetic variants, but little is known regarding this. In the first Aim, we will examine associations between energetic factors and cancer-related biomarkers in about 750 women (includinq 25% African American women) in the Nurses'Health Study. Energetic factors will include: (1) energy expenditure measured by doubly labeled water (DLW);(2) dietary insulin demand measured by insulin index and insulin load;(3) physical activity assessed by repeated accelerometer measurements;and (4) sleep duration assessed by two 1-week sleep logs. Cancerrelated biomarkers will include (1) insulin-IGF axis components (fasting insulin, proinsulin, C-peptide, IGF-1, and IGFBP-3);(2) adipokines (total and free leptin [the ratio of leptin to soluble leptin receptor - sOB-R] and adiponectin);and (3) sex hormone-binding globulin (SHBG) and estradiol. In the second Aim, we will examine the relationships between neighborhood SES and built environment (assessed by the county sprawl index) and cancer-related biomarkers, and delineate the pathways linking these macro-level variables, energetic factors, biomarkers, and obesity. In the third Aim, we will examine whether genetic factors related to insulin resistance or insulin secretion modify the associations between behavioral (dietary insulin demand, physical activity, and sleep duration) and macro-level (neighborhood SES and built environment) factors and risk of obesity and long-term weight gain among 8,000 men and women in the Nurses'Health Study and Health Professionals Follow-up Study with available genome-wide association studies (GWAS) data. The findings from this study will not only provide insights into social, behavioral, and biological pathways underlying the relationship between energy balance and cancer risk, but also facilitate development of multi-tiered risk reduction strategies spanning diet and lifestyle modification to urban planning and community outreach for obesity and cancer prevention. Because the proposed study is based on well-established ongoing cohorts, and detailed measures of energetic factors (DLW, diet, physical activity, and sleep) and blood collection have been funded through a 2-year stimulus grant (2009-2011) by NCI, it is extremely cost-effective and timely.