Breast cancer (BC) is the second most common cancer diagnosed in American women and is also the second leading cause of cancer death in women. Compared to Caucasian American (CA) women, African American (AA) women display earlier onset of BC, are more likely to be diagnosed with metastatic types of BC at the time of presentation, and have a significantly higher mortality rate. Our long term goal is to reveal the biological factors underlying racial disparities in BC outcomes and thereby facilitate development of novel clinical applications to eliminate such disparities. The biological factors that mediate BC racial disparities remain largely unknown. We performed a bioinformatic analysis using a dataset from TCGA (NCI) and unexpectedly identified that SEMA6D expression in BC tissues from AA women was significantly lower than in CA women. The low expression level of SEMA6D correlates significantly with poor survival of BC patients, and the association is more dramatic for patients with triple negative receptor status (ER, PR and HER2). In further support of our initial finding, examination of multiple datasets from NCBI GEO confirmed that expression of SEMA6D is significantly reduced in BC tissues compared to normal tissues. Our initial functional assay indicated that SEMA6D represses BC cell metastasis both in vitro and in vivo. SEMA6D is a member of the Semaphorin family of signaling molecules and its functions in BC pathogenesis have never been reported in the literature. Based on results from both our bioinformatic and functional analyses, we hypothesize that SEMA6D inhibits BC metastasis and differential expression of SEMA6D is a causative factor for outcome disparities observed in AA versus CA patients. We will initially test our hypothesis through the following two aims In Aim 1; we will determine the in vivo activity of SEMA6D in repressing BC metastasis. In Aim 2, we will characterize the potential mechanism for the differential expression of SEMA6D observed in AA versus CA patients. In this study, we will examine for the first time the role of SEMA6D in repressing BC metastasis. This study represents the first to connect Semaphorin signaling with BC racial disparities. Accomplishing this study will provide crucial clues for understanding the biological basis for racial disparities in BC and will facilitate development of novel diagnostic/therapeutic approaches to eliminate such disparities. Our preliminary studies provide a strong foundation for our central hypothesis and demonstrate that we have established the necessary tools for the proposed work. The tightly focused nature of the proposed studies will allow us to address these questions within the time-frame of this grant.