TNBC is arguably the most deadly BrCa subtype with higher prevalence in pre-menopausal women and in women of African descent. We know that the combined TNBC prevalence and poor treatment options are a likely cause of persistently higher mortality rates in African Americans compared to European Americans in the US. However, we have shown that within African Americans, disparities in BrCa survival are more pronounced within the TNBC category compared to the ER positive groups. These data indicate that unique mechanisms are operating in either tumor biology or host response in women of African descent. The ancient and African- specific Fy- allele alters the regulation of DARC/ACKR1, an atypical chemokine receptor, in a tissue-specific fashion beyond the previously described RBC phenotype. This implicates DARC/ACKR1 in various altered phenotypes in these ancestry groups, specifically as it relates to chemokine regulation. This project will test the hypothesis that DARC expression in tumor cells alters tissue chemokine levels to modify the host immune response to tumorigenesis, and that absence of DARC expression on blood cells as a result of the African-specific Fy- allele alters circulating chemokine levels, altering the tumor microenvironment and enhancing tumor aggression. Specifically we will; 1- Determine if DARC tumor expression associates with ancestry and altered host immune responses in a pilot BrCa cohort of African Americans and European Americans and 2- Determine if loss of DARC on bone-marrow-derived (bmd) blood cells alters chemokine profiles and tumor immune response, using pre-existing transgenic C3- 1Tag BrCa and AckR1-/- mice.
This proposal addresses the disparities of breast cancer mortality in African Americans compared to European Americans and will provide information that defines a genetic mechanism to account for these differences. The results from this study will be used to develop in future studies to a novel prognostic and therapeutic targets for personalized medicine in these populations.