PROJECT SUMMARY Breast cancer (BC) is not only a heterogenous disease by itself but it also has a differential racial impact. Prognostically, it has an inferior outcome in women of African American (AA) descent as compared to European American. BC in women of African ancestry presents at a younger age and is associated with more advanced disease and higher mortality rates as compared to breast cancer in age-matched patients of EA or Asian ancestry (AsA). Several factors, including ethnicity and social determinants of health factors (SDOH), including obesity adds to the complexity to nature of the disease. The chronicity of these environmental stressors has played a determinate role in racial/ethnic BC inequities. We propose to investigate the intersection of SDOH and biological determinants of tumor biology by examining the convergence of obesity- and ancestry-related inflammatory factors and their consequences on tumor genomic and immunological landscapes. In this project, the association of the obesity-associated inflammatory signature for those with African ancestry in admixed-African BC patients in Black Belt Alabama will be explored. We will determine genetic ancestry-associated differences in tumor immune microenvironments linked to systemic inflammation and obesity. To do so, we have adopted the Tuskegee Total Cancer Care protocol, which partners with local health care providers and patients with the goals of using longitudinally collected data and biospecimens to develop an evidence-based approach that meets the needs of minority patients. We will work through three distinct specific aims, utilizing case-control studies, which will flow hierarchically from broad patient-centered population-level factors to systemic-and genomic-level factors to characteristics tumors and heterogeneous cell types within the tumor. These will help define distinct risk factors that capture both the social and biological mechanisms that underlie tumor phenotypes. Integration of these data will provide new opportunities to develop interventions that, on a community level, will help to overcome immune and inflammation-driven/obesity-related BC progression