PROJECT SUMMARY Breast cancer (BC) is the most commonly diagnosed malignancy and second leading cause of cancer-related deaths among women in the US. Among all BC cases, black women suffer higher incidence of poor-prognosis BC subtypes and worse stage-specific mortality. Growing evidence supports the importance of the immune component of the BC microenvironment (BCME) in clinical outcomes. However, despite an abundance of clinical trials and retrospective studies investigating the immune microenvironment in BC, biomarkers of immune response are lacking and there is limited research regarding differences by race. By studying immune cells and immune-related gene expression alone, the positive prognostic utility of tumor infiltrating lymphocytes in BC thus far has been limited to triple negative and HER2-positive subtypes. The identification of a tumor-cell specific biomarkers associated with BC immunogenicity could help identify additional candidates for immunotherapy. In this regard, TP53 mutations are the most frequently occurring mutation in BC, vary in frequency by race, and are associated with immune response in several tumor types. However, literature addressing the association between TP53 dysfunction and BC immunogenicity is conflicting, and has never been studied in the context of racial disparities. Thus, whether and how immune response differs by race, p53 functional status and survival represents a critical knowledge gap in BC. To address this gap, I will leverage two major BC cohorts rich in molecular, histological, clinical and epidemiological data: 1) the Carolina Breast Cancer Study (CBCS), a large population-based study designed to investigate racial disparities in BC, and 2) The Cancer Genome Atlas (TCGA) BC cohort, a well-known study with multiple data platforms for each sample. Using these resources, I have obtained preliminary data suggesting that gene expression related to adaptive immune response is enriched in breast tumors from black women vs non-black women, and that dysfunction in the p53 pathway is associated with this response. Based on these findings, I hypothesize that differences in the immune BCME contribute to racial disparities and survivorship outcomes, and that p53 function is a tumor-intrinsic mediator of this process. I will test my hypothesis with two specific aims. In aim 1, I will characterize immune BCME phenotypes using RNA expression profiling and immunohistochemistry and will evaluate associations with race, age, tumor intrinsic subtypes and survival. In aim 2, I will investigate the relationship between TP53 functional status and immune phenotypes in association with race and tumor intrinsic subtype. Given the low representation of black women in clinical trials and gene expression studies, this will be the largest study of its kind to investigate the immune BCME in black and non-black women. The results of this work will collectively elucidate how the immune BCME contributes to tumor progression leadi...