Abstract PR-08: Diabetes affects metabolism, redox signaling, DNA repair capacity and mutational burden in breast cancer

Abstract

Abstract Comorbidities disproportionately affect underserved populations. Diabetes can increase cancer risk and decreases breast cancer survival. Diabetes-associated breast cancer risk impacts African American women more than European Americans. The goal of this study was to understand how diabetes may shape breast tumor biology. We performed an RNA and whole-exome sequencing (WES) analysis, together with global metabolomics, of matched breast tumors from patients with or without diabetes, with the majority being of African American descent. Additionally, as an experimental model, we generated mammary xenografts following orthotopic injection of breast cancer cells (MDA-MB-231, MDA-MB-468, and HS578T) into the mammary fat pad of diabetic mice (NOD.Cg-Rag1 tm1Mom Ins2 Akita Il2rg tm1Wjl/SzJ). After 4-6 weeks we collected the tumors and performed RNAseq and metabolome analysis. Analyzing the metabolome profile of both human breast tumors and xenografts, we observed a distinct metabolite pattern in diabetic breast tumors and diabetic mice. The key observation was the enrichment of food and microbial-derived metabolites under diabetes, indicating that diabetes may promote the accumulation of these metabolites in breast tumors. Next, we analyzed the RNAseq data from the same tumors and xenografts. Here, we applied Gene Set Enrichment Analysis (GSEA) with the transcriptomic data to find specific pathways activated under diabetic conditions. GSEA indicated the enrichment of gene signatures related to mesenchymal and stem cell-like phenotypes both in the patient tumor and xenografts under diabetes. Additionally, we discovered an enrichment of the reactive oxygen species (ROS) pathway in diabetic tumors and xenografts. Consistent with this observation, treating breast cancer cells (MDA-MB-231 and HS578T) with high glucose (25mM) increased superoxide radical production in these cells. Since higher ROS levels could cause DNA damage, we examined DNA damage in breast cancer cells cultured under high glucose. Here we observed an increase in DNA damage under high glucose as indicated by robust nuclear γH2AX and 53BP1 immunostaining. An additional KEGG analysis indicated the inhibition of various DNA repair pathways (e.g. base-excision, nucleotide excision, and mismatch repair) in breast tumors and xenografts. Corroborating this finding with our WES data, we observed a significant enrichment of several mutational signatures (SBS5, SBS15, and SBS30 DNA repair deficiency signatures) in breast tumors of diabetic patients, suggesting that diabetes may interfere with DNA repair pathways in breast tumors. Taken together, this study suggests that diabetes promotes a mesenchymal and stem cell-like phenotype in human breast tumors with higher oxidative stress & DNA damage and a decreased DNA repair capacity. Our data further indicate that breast tumors from diabetic patients may have an increased susceptibility to DNA damage response inhibitors like PARP inhibitors. Citation Format: Gatikrushna Panigrahi, Tiffany Dorsey, Wei Tang, Julian Candia, Amy Zhang, Stefan Ambs. Diabetes affects metabolism, redox signaling, DNA repair capacity and mutational burden in breast cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PR-08.