Files
Abstract
Breast cancer (BC) is a heterogeneous disease that leads to varied molecular subtypes and distinct clinical outcomes. Tumor heterogeneity, which is in part influenced by genetic ancestry, contributes to the racial disparities that have persisted in BC for over 30 years. When investigating race-specific differences in the breast tumor microenvironment (TME), we believe that chemokine receptors, such as Atypical Chemokine Receptor 1 (DARC/ACKR1), play an integral role in regulating chemokines and immune cell migration in circulation and in the TME, ultimately influencing tumor progression. DARC/ACKR1 specifically plays an important role in ancestry-related differences in BC due to an African-specific ancestral allele (Duffy-null) that is nearly fixed in Sub-Saharan African populations, and present in 60-70% of African-Americans. To better characterize the effects of this receptor and this variant in BC, we collected ethnically diverse biospecimens from BC patients from both the United States and African countries, to perform comparative characterizations of chemokine and immune cell signatures. By employing immunohistochemical (IHC) and immunofluorescent techniques to determine DARC/ACKR1 protein expression on tumors, in addition to Luminex protein multiplexing assays to determinecirculating chemokine protein concentrations, and extensive genotyping for Duffy-null and other variants associated with BC risk in our cohort, we were able to determine that DARC/ACKR1 is expressed on breast tumor epithelial cells, its expression on tumors is significantly correlated with increased overall and relapse-free survival, and it is significantly associated with the pro-inflammatory chemokines, CCL2 and CXCL8 in BC. From our IHC analysis, we identified distinct immune cell signatures, including the presence of B-cells and dendritic cells in DARC/ACKR1 positive tumors only, in addition to variable levels of circulating chemokines, where those with the Duffy-null mutation exhibited significantly decreased levels of CCL2, and were also more likely to be diagnosed with the more aggressive BC subtype, triple-negative breast cancer. Overall, our analyses support the hypothesis that tumor-specific DARC/ACKR1 plays a vital role in chemokine and immune cell regulation in women with BC, and that the presence of the Duffy-null allele could lead to more disparate outcomes for women of African ancestry.