This career-development award will provide me with specialized knowledge and skills in cancer molecular and genetic epidemiology, biocomputational techniques, and genomic statistical approaches. The research will provide the mentored guidance and collaboration I need to begin my independent academic career as a gene– environmental cancer epidemiologist. The overarching goal of my proposed research is to understand the influence of gene–lifestyle interactions on the pathways connecting insulin resistance (IR) and breast cancer among postmenopausal women, a population highly susceptible to breast cancer. Obesity is a well-established risk factor for postmenopausal breast cancer; obesity–insulin connections in particular have gained growing attention over the last decade as potential factors of cancer development and prognosis. Although IR, obesity status, and obesity-related lifestyle factors for postmenopausal breast cancer are well established, the genetic basis of IR that is associated with breast cancer is largely unknown. For genetic mutation–behavioral interactions, no studies to date have explored the interacting role of obesity status and correlated lifestyle factors in these pathways among IR-related genetic variants, IR traits (e.g., IR), and postmenopausal breast cancer risk. Further, without genetic alterations, IR genes' functions can be changed, affecting breast cancer risk and prognosis. DNA methylation, one of these epigenetic modifications, plays a key role in epigenetic silencing of transcription. Aberrant DNA methylation has frequently been found in cancer-related genes, leading to a cell shift to a state of high proliferation favoring cancer development and progression. DNA methylation studies have explored associations with breast cancer, but IR genes' methylation studies on postmenopausal breast cancer prognosis are scarce. To address these gaps, the specific aims are 1) to evaluate the influence of obesity status and lifestyle factors (e.g., high-fat diet and low physical activity) as effect modifiers of the associations among IR-relevant genetic variants, IR-related traits, and breast cancer risk, 2) to perform pathway-based association analysis between IR genes and breast cancer risk, stratifying by obesity and relevant lifestyle factors, and 3) to determine whether IR genes' methylation markers are associated with breast cancer prognosis and whether these phenomena differ by obesity status. These specific aims will be achieved by using existing large-scale cohort data of postmenopausal women from 6 substudies of the Women's Health Initiative Database for Genotypes and Phenotypes Study and the Cancer Genomic Atlas breast cancer data, with available biochemical and genotyped samples. Elucidating how obesity and correlated lifestyle factors intermingle with pathways of IR, the relevant genes (with genetic and epigenetic changes), and breast cancer may yield valuable new insight into the study of gene–lifestyle interactions. T...