In line with one of the NCI's "provocative questions," the aim of this study is to uncover potential mechanisms linking obesity and breast cancer. This study will also explore the association between adiposity-related biomarkers within the breast and the triple-negative breast cancer (TNBC) phenotype. Obesity is clearly associated with poorer breast cancer prognosis, and while the underlying mechanisms are unclear, evidence supports the involvement of adipokine biomarkers (adiponectin, leptin and their receptors). Given that African American (AA) women tend to have higher prevalence rates of obesity (which translate into substantially lower circulating adiponectin and higher leptin concentrations) and are more frequently diagnosed with aggressive breast tumors, at a younger age, than white women, the adipokines and their respective receptors are conceivably related to breast cancer disparities. However, investigators examining associations between adipokines and breast cancer have generally assumed that blood concentrations are sufficient surrogates for concentrations within the breast. Thus, the goal of this proposal is to determine the associations among breast adipokine and adipokine receptor expression and genetic variation, and breast tumor clinicopathological characteristics (eg, size, grade and breast cancer molecular subtype [ER+/PR+/Her2-, ER+/PR+/Her2+, ER-/PR-/Her2+, ER-/PR-/Her2-]). Additionally, this study will comprehensively examine the correlates of the TNBC phenotype and explore racial differences, which are hypothesized to be related to adiposity and breast adipokine expression and genomic profiles. For this proposal, questionnaire data, formalin-fixed paraffin-embedded (FFPE) breast tissues, and genomic data from a cohort of 1100 breast cancer cases, nested in the well-established Women's Circle of Health Study (WCHS) will be used to address the following specific aims: (1) to examine the associations among breast tissue adipokine and adipokine receptor expression profiles and breast tumor clinicopathological features among invasive BC cases; (2) to assess the associations among genetic variation in genes encoding the adipokines and their receptors (ADIPOQ, LEP, ADIPOR1, ADIPOR2 and LEPR), protein and mRNA expression profiles, and tumor clinicopathological features among invasive BC cases; and (3) to assess the associations among adiposity, adipokine protein and mRNA expression profiles, and the TNBC phenotype and to explore racial differences in the risk factors for TNBCs. In Aim 1, immunohistochemical and multiplexed gene expression assays will be used to assess protein and mRNA expression, respectively, of the adipokines and their receptors in breast tumors (using FFPE tissues) among a cohort of 1100 AA and white invasive breast cancer cases enrolled in WCHS. In Aim 2, a selected panel of functional single-nucleotide polymorphisms (SNPs) in the ADIPOQ, LEP, ADIPOR1, ADIPOR2 and LEPR genes will be genotyped through high-throughput genomic techniques, with priority given to SNPs previously shown to be associated with adipokine concentrations, breast cancer risk or prognostic indicators. In Aim 3, risk factors of the aggressive TNBC phenotype will be comprehensively examined, with emphasis on anthropometrics, body composition, lifestyle factors, and molecular characteristics associated with adiposity (including adipokine and adipokine receptor protein and mRNA expression, and adipokine SNP genotypes examined in Aims 1 and 2). Findings from this study will address several important gaps in current knowledge related to the characterization of TNBCs, exploration of racial differences in TNBC risk factors, and understanding the role of adiposity-related biomarkers within the breast microenvironment and their associations with breast tumor characteristics. Furthermore, this study will add novel data on breast tissue-specific adipokine genotype-phenotype associations and generate new hypotheses about the role of genetic variation in interindividual differences of breast biomarkers. The Principal Investigator previously obtained broad training in molecular epidemiology and solid training in cancer disparities and community-based participatory research. In order to conduct cutting edge research that will bridge the gap between laboratory-based and community-based studies, and promote the translation of laboratory findings to the population and vice versa, she will obtain additional multidisciplinary mentorship and rigorous training that will further advance her skill sets in molecular epidemiology and contemporary molecular techniques as well as in clinical/translational research. As a result of her unique training experiences to date, coupled with the intensive training plan outlined in this K01 application, the PI will be well-equipped to successfully transition into an independent investigator making important contributions to impact the fields of molecular epidemiology and cancer disparities, with emphasis on uncovering mechanisms that link obesity and cancer, which has direct relevance to the mission of the National Cancer Institute.