Characterization of the Metabolome of Breast Tissues from Non-Hispanic Black and Non-Hispanic White Women Reveals Correlations between Microbial Dysbiosis and Enhanced Lipid Metabolism Pathways in Triple-Negative Breast Tumors

SIMPLE SUMMARY: We previously showed that breast tumor tissues from women display an imbalance in abundance and composition of microbiota compared to normal healthy breast tissues. It is unknown whether these differences in breast tumor microbiota may be driven by alterations in microbial metabolites, leading to potentially protective or pathogenic consequences. The aim of our study was to conduct global metabolic profiling on normal and breast tumor tissues to identify differences in metabolite profiles and to determine whether breast microbial dysbiosis may be associated with enrichment of microbial metabolites in triple-negative breast cancer (TNBC) which disproportionately affects women of African ancestry. We observed significant correlations between elevated lipid metabolism pathways and microbial dysbiosis in TNBC tissues from both non-Hispanic black and white women. This is the first study to report an association between breast microbial dysbiosis and alterations in host metabolic pathways in breast tumors, including TNBC, of non-Hispanic black and non-Hispanic white women. ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that is non-responsive to hormonal therapies and disproportionately impact women of African ancestry. We previously showed that TN breast tumors have a distinct microbial signature that differs from less aggressive breast tumor subtypes and normal breast tissues. However, it is unknown whether these differences in breast tumor microbiota may be driven by alterations in microbial metabolites, leading to potentially protective or pathogenic consequences. The goal of this global metabolomic profiling study was to investigate alterations in microbial metabolism pathways in normal and breast tumor tissues, including TNBC, of non-Hispanic black (NHB) and non-Hispanic white (NHW) women. In this study, we profiled the microbiome (16S rRNA) from breast tumor tissues and analyzed 984 metabolites from a total of 51 NHB and NHW women. Breast tumor tissues were collected from 15 patients with TNBC, 12 patients with less aggressive luminal A-type (Luminal) breast cancer, and 24 healthy controls for comparison using UHPLC-tandem mass spectrometry. Principal component analysis and hierarchical clustering of the global metabolomic profiling data revealed separation between metabolic signatures of normal and breast tumor tissues. Random forest analysis revealed a unique biochemical signature associated with elevated lipid metabolites and lower levels of microbial-derived metabolites important in controlling inflammation and immune responses in breast tumor tissues. Significant relationships between the breast microbiome and the metabolome, particularly lipid metabolism, were observed in TNBC tissues. Further investigations to determine whether alterations in sphingolipid, phospholipid, ceramide, amino acid, and energy metabolism pathways modulate Fusobacterium and Tenericutes abundance and composition to alter host metabolism in TNBC are necessary to help us understand the risk and underlying mechanisms and to identify potential microbial-based targets.