The DARC Side of Breast Cancer Project
Breast Cancer Disparities
There is a lingering higher Breast Cancer mortality rate in African Americans, compared to Caucasians.
Disparities are caused by a number of interacting factors. There is a pressing need for research investigating population-specific genetic and environmental factors that explain the disproportionate incidence of aggressive Breast Cancer (BrCa) in young Afr. American (AA) women.
Recently, a new appreciation of human molecular diversity among genetic ancestry groups has ignited investigations of biological causes of cancer disparities. These studies have revealed a bias of certain BrCA subtypes with a higher prevalence in specific ethnic groups that correlates with negative clinical outcomes. Specifically, The ethnic disparities of higher mortality rates and more frequent occurrence of triple negative breast cancer (TNBC)[1, 2] subtypes in both Africans and African Americans[3-5] as an early onset disease suggests there is a genetic component driving a distinct susceptibility within these populations.
TNBC is defined by the absence of Estrogen Receptor (ER), Progesterone Receptor (PR) and HER2/Neu gene expression. The current Standard of Care for new BrCA diagnoses is to assess the over-expression of these genes in order to determine the proper course of treatment and the eligibility of patients for targeted therapies.
Two of these genes are currently basis of targeted therapy drugs that effectively cure (no recurrence) over 90% of women with Luminal (ER positive) and HER2 positive tumor subtypes. However, there are no targeted therapy options for women with TNBC and the bleak prognosis (less than 40% 5-year-survival rates) is only darkened by the fact TNBC is one of the most aggressive subtypes. A lingering challenge has been defining the mechanisms that derive this subtype. The key to identifying this mechanism lies in the proper investigation of populations that have the highest prevalence of the subtype.
Some Findings from the Davis Lab:
Epigenetic regulators help control the expression of cancer genes. We found that one such regulator (CARM-1) displays unique expression patterns in cancers derived from people of African descent. This establishes a possible mechanism of differential gene regulation that we will further investigate on the genome level.
A brief history of the DARC gene and its role in immunobiology.
The Duffy Antigen Receptor for Chemokines (DARC) gene has been extensively studied in infectious disease research, for its role in malaria infection.
Its expression on red blood cells is the gateway of the Plasmodium parasite to enter the host. DARC has two splice forms which result in two protein isoforms. The Duffy Null (Fy-) allele of DARC, which has reached near fixation in certain African populations, confers an immunity to malaria, as it removes the expression of DARC on red blood cells. Specifically, the polymorphism (rs2814778) is a T to C substitution that resides in the promoter region of the DARC2 (B isoform), removing a GATA3 response element resulting in lack of DARC erythrocyte expression, (5) and it resides in the 5’ Untranslated Region (UTR) of the DARC1 isoform and the consequence to this isoform is unknown. The Fy- allele is very rare in populations outside of Africa; with an average 98% allele distribution in Africa, over 80% in AA and under 20% in Caucasians.
Recent displacement of significant numbers of Africans to North America has resulted in a unique admixed population of both African and European descent, African-Americans (AA). Our lab has recently established that the DARC isoforms have a distinct pattern of expression in HAPMAP lymphoblast lines derived from individuals of African, African American and European descent. Aside from its role in malaria, DARC is a ubiquitously expressed atypical chemokine receptor (aka ACKR1), which modulates chemokine gradients between tissues and blood and so mediates the influx of neutrophils and monocytes from blood vessels into tissues.
The search for genetic associations of cancer risk that could explain disparities in African lineages has not been very successful. One confounding variable is proper population stratification that both controls for ancestry and harnesses the power of this variable to identify a genetic modifier that exclusively confers risk to a specific group. Ancestrally Informative Markers (AIMs) are useful in quantifying an individual’s ancestry[9, 10]; however, without applying ancestry information to individual gene loci[11, 12], simply modeling ancestry in the association analysis may actually reduce the significance of real risk alleles that only exist in a certain ancestry group[11-13, 14 ]. In this way, all-inclusive GWAS analyses may have ignored SNPs we need to find.
We hypothesize that specific ancestry groups, due to the Fy- mutation, may show distinct immunological responses that contribute to the development of breast cancer types in these populations.
DARC and chemokines in cancer progression – the tumor microenvironment.
The overall objective of this project is to establish how women of African (Afr.) genetic ancestry, due to a fixed genetic polymorphism of the Duffy Antigen Receptor for Chemokines (DARC) gene occurring in recent Afr. lineages (Duffy null allele or Fy-), have a distinct immunological mechanism that contributes to the development of aggressive breast cancer types in these populations. DARC is a ubiquitously expressed atypical chemokine receptor (aka ACKR1), which modulates chemokine gradients between tissues and blood and so mediates the influx of neutrophils and monocytes from blood vessels into tissues. We have recently determined that the Fy- allele influences the relative expression levels of DARC isoforms, which are unique gene products with the potential to interact with different chemokines in an isoform-specific fashion. Previous studies implicate DARC, a pro-inflammatory cytokine receptor, in lung cancer etiology, BrCa progression by in vitro studies and specific allele association with BrCa patient survival. However, no study delineates distinct interactions between DARC isoforms and chemokine binding partners, or how these isoforms may contribute to epithelial DARC expression and its influence on tumor formation and progression.
Some of our recent findings....
DARC is expressed differentially among tumor subtypes and co-localizes with a pro-inflammatory chemokine, CXCL8
DARC is displays differential expression of its isoforms among genetic ancestry groups (see our recent paper in PLoS One)
In a recent publication, we have shown that the DARC transcript isoforms are distinctly expressed in people of African Ancestry, due to the Duffy null mutation. This exciting finding has far-reaching implications; including, a distinct regulation of chemokine levels in African, African-Americans and Afro-Latino populations that will ultimately re-define immune responsiveness in these groups.
We are busy in the Informatics Lab!! We have some data from the 1K Genomes project that indicates there are unique alleles prevalent in populations that are under similar selective pressures, due to tropical vector-borne pathogens, that may reveal additional Duffy antigens.... we'll keep you posted!