Abstract B101: Obesity mediates altered triple-negative breast cancer tumor biology in African American women independent of ancestry
Authors: Bedi Deepa , Martini Rachel , Davis Melissa B. , Yates Clayton 
Published: December 2023

African American (AA) breast cancer (BC) is associated with a higher incidence of aggressive BC phenotypes at younger age, higher grade of tumor as compared to BCs of age-matched patients of European American (EA). For AA women, there is a higher frequency of the more aggressive TNBC subtype and of the PAM50-molecular basal subtype. AA tumors are enriched for inflammatory and immune pathways, implicating inherited susceptibility associated with African ancestry. Obesity induces a state of low-grade inflammation. AA women tend to be more obese than EA and have elevated a inflammatory markers, including CRP, IL6, and IL1. Since inflammation related to obesity is a reflection of dysfunctional adipocyte biology, we used dataset GSE88837 to perform in silico analysis of gene expression changes in visceral adipose tissue for AAs and EAs. AA adipose tissue is more inflamed than EAs at the same level of obesity (BMI&gt;30). There was a high expression of secreted mediators causing systemic inflammation, including heat shock protein 60 (HSPD1), CXCL1, S100A9, and SPP1.  VEGFA, S100A9, and SPP, tumor-promoting angiogenic mediators, were higher in obese AAs than EAs. These data indicate that obesity enhances inflammation in visceral adipose tissue of AAs. We performed in silico analysis of dataset GSE78958, of 400 BC patients annotated for race, BMI, and hormone receptor expression. We analyzed BC patients for differential gene expression, PAM50 subtype, tumor stage and grade, based on race and BMI. AA women have a higher BMI (48.9%) than EA women (32.3%) and a higher percentage of poorly differentiated tumors (51.1%) than EAs (40.6%).  AA women with BMI &gt;30, had more basal-like tumors (34.8%) than EA women (19.3%). These analyses confirm that excess adiposity promotes the basal BC phenotype. With BMI &gt;30 as a criterion for obesity, the GSE78958 dataset containing BCs for 96 AA and 200 EA patients was analyzed for differences in gene expression. DEGs showed upregulation of T cell exhaustion marker PTPN22 and LAIR2. The metastasis and proliferation promoting chemokines CXCL1, CCL2, CXC12, CXCR4, and S100A9 were higher in the BCs of obese AAs, than BCs of non-obese AAs. Stemness related genes, STAT1, SOX4, and KLF4, were higher in BCs of obese AAs. CD163-expressing M2 macrophages were higher in BCs of obese AAs. Our group showed that there was a considerable overlap of genes among African and AA cases, but there were some non-overlapping genes indicating that ancestry alone cannot explain the genetic diversity in the tumor phenotype of AA patients. The divergence was largely driven by an upregulated gene signature found among AAs and not seen among African patients. GSE78958 (obesity BC dataset) was mapped for ancestral correlation of altered genes in the AA BC dataset. Ancestry mapping showed an inverse correlation of HSPD1 with ancestry. Obesity upregulated HSPD1 in BCs of AAs as well as in AA adipose tissue and decreased the probability of survival for women of AA ethnicity, suggesting delineation of ancestry-specific and race-specific effects.

Citation Format: Deepa Bedi, Rachel Martini, Melissa B. Davis, Clayton Yates. Obesity mediates altered triple-negative breast cancer tumor biology in African American women independent of ancestry [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B101.