Abstract 1962: Oncologic anthropology-impact of Duffy adaptive trait on breast epithelial and tumor cell biology

Abstract

Abstract Adaptation to diverse environments during human evolution including those conditions that favor certain infectious diseases to become endemic in a region has resulted in natural selection of genetic variants. These variants remain fixed in current day populations despite changes in the environment. At least 20 such variants, also called adaptive traits, have been described to date and Duffy phenotype is one among them. Individuals in sub-Saharan Africa carry an inactivating mutation in a gene called atypical cytokine receptor 1 (ACKR1 or DARC) and this phenotype is called Duffy-phenotype. ACKR1 is a decoy receptor for CCL2 and IL-8 (CXCL8) and limits the activity of these cytokines. The Duffy-null phenotype confers protection against malarial infection. However, recent studies suggest that breast cancers in Duffy-null women display a distinct immune profile and have worse outcomes, possibly due to altered signaling by cytokines/chemokines. Using our institutional resource of breast tissues from >5000 healthy women, we have initiated studies to examine the impact of adaptive traits on normal breast and breast cancer biology. Towards this goal, we have created breast epithelial cell lines from Duffy wild type and Duffy-null/heterozygous carriers, all of African ancestry. ACKR1 is expressed in breast epithelial cells of Duffy-wild type but not in Duffy-null carriers. Breast epithelial cell lines as well as their transformed variants from Duffy-null/heterozygous carriers contained elevated levels of phosphorylated cMET(Y1349) and pERK(T202/Y204) compared to cell lines from Duffy-wild type carriers. Transformed Duffy-wild type and Duffy-heterozygous cells generated adenocarcinomas in NSG mice, which indicates that our model system closely recapitulates breast cancers in human. Cell lines created from Duffy-heterozygous tumors compared to Duffy-wild tumors displayed elevated pERK levels. Duffy phenotype also affects parainflammatory signals from transformed cells as tumor-derived cells from Duffy-null/heterozygous carriers expressed higher levels of IGFBP2 compared to tumor-derived cells from non-carriers. Additional studies are underway to determine whether Duffy phenotype alters sensitivity to chemo and targeted therapies. Collectively, these results suggest that adaptive traits alter epithelial cell intrinsic signaling pathways, which may affect tumor growth patterns, tumor microenvironment, and potentially sensitivity to specific therapies. Citation Format: Poornima Bhat-Nakshatri, Brijesh Kumar, Madhura S. Shukla, Katie Batic, Henry Mang, Rana German, Anna Maria Storniolo, Harikrishna Nakshatri. Oncologic anthropology-impact of Duffy adaptive trait on breast epithelial and tumor cell biology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1962.