Abstract B24: Regulation of DARC isoforms among ancestry groups and associations with aggressive breast cancer subtypes

Biological mechanisms that drive disparate incidences of aggressive breast cancer in women of African descent are still largely unknown. Despite the fact that White women are more often diagnosed with breast cancer, African-American women have more severe cases and more often die from their breast cancer. Certain clues surrounding the tumor behavior and aggressive nature of cancers in African Americans point to physiological contexts, perhaps even the immunological microenvironment of the cancer sites. We hypothesize that higher mortality rates, coupled with lower incidence of breast cancer in this population, compared to white women, suggests the susceptibility is not necessarily a predisposition to acquire cancer, but that once a malignant cell is formed, the physiological make-up of these individuals somehow drives the aggressive nature of the tumors. This would explain the poor prognosis and higher mortality rates. We further hypothesize that chronic pro-inflammatory status, and altered chemokine profiles in this population are a key to tumor progression disparities. These disparities are likely due to specific genetic differences. Specifically, we are investigating the role of the Atypical Chemokine Receptor (ACKR1/DARC) gene and its isoforms in influencing a woman9s chance of developing aggressive breast cancer subtypes. We aim to demonstrate that altered expression of DARC isoforms play a role in breast cancer severity and tumor aggression by regulating the infiltration of specific immune cell types into the tumor environment, by altering the levels of specific chemokines in the breast. We are investigating how the Duffy null allele, prevalent in all women of African descent, affects the ability of regulatory transcription factors to properly express ACKR1/DARC in epithelial and lymphoblast cells. GATA1 has been shown to regulate DARC in erythrocyte lineages; however, our previous findings indicate that DARC expression on epithelial (tumor) cells correlate with specific immune cell infiltrates. We have found that there are significant differences in epithelial Gata3 expression, correlating with DARC expression levels among ancestry groups. Using bioinformatics techniques, and ChIP-PCR we aim to define more precisely the transcription factors responsible for DARC isoform regulation. Specifically, by integrating expression data and interaction data with databases such as HEFalMp and identifying enrichment of biological processes with tools such as DAVID, we will identify additional candidate transcription factors by measuring associations of candidate gene expressions with DARC, we will define biological pathways related to immunological and inflammatory responses and test the ability of the highest priority candidate transcription factors to regulate DARC using siRNA techniques. Once we know what transcription factors are involved with epithelial expression of DARC, we can develop tools to further investigate how DARC plays a role in tumor progression in women of African descent. Citation Format: Kathryn Vollum, Rebekah Hutchins, Andrea M. Brown, Crystal Perez, Melissa B. Davis. Regulation of DARC isoforms among ancestry groups and associations with aggressive breast cancer subtypes. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B24.