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. This study will also allow researchers to target efforts to those with risk
genotypes to promote behavioral and pharmacotherapeutic (e.g., demethylating agents) interventions, to reduce
IR and modify insulin signaling, thus reducing breast cancer risk and poor prognosis in postmenopausal women.