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

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.

Biological Basis of Breast Cancer-Related Disparities in Precision Oncology Era

“…Both tumor and normal tissue adjacent to tumor (NAT) samples emphasized a specific microbiota in both NHB and NHW women, whereas, when compared to a matching NAT area, the microbial diversity in NHB TNBC cancer tissue was much reduced [252]. Smith et al (2022) reported that TNBC has a specific microbiota that differs from the less aggressive BC subtypes, emphasizing a correlation between host metabolic process changes and breast microbial dysbiosis in NHB and NHW women's breast cancers [253]. Thus, potential race-specific microbial biomarkers of BC correlate to genes involved in tumor aggressiveness, angiogenesis, migration and metastasis, as well as oncogenic signaling pathways GLI and Notch in a specific manner [36].…”

Exploring the human microbiome – A step forward for precision medicine in breast cancer

“…NGS technologies allow for rapid and comprehensive sequencing of the genetic material of the gut microbiome, revealing previously unknown microbial diversity and functional pathways 117,118 . This has led to the identification of specific microbial taxa and functional pathways associated with breast cancer development, such as changes in the abundance of certain bacteria or alterations in the production of specific metabolites 119 . Similarly, genome sequencing and single‐cell sequencing enable researchers to identify specific genetic pathways and interactions between microbial species in the gut that may contribute to breast cancer development 120 .…”

“… 117 , 118 This has led to the identification of specific microbial taxa and functional pathways associated with breast cancer development, such as changes in the abundance of certain bacteria or alterations in the production of specific metabolites. 119 Similarly, genome sequencing and single‐cell sequencing enable researchers to identify specific genetic pathways and interactions between microbial species in the gut that may contribute to breast cancer development. 120 By identifying these pathways and interactions, researchers may develop targeted therapies that modulate the gut microbiome to prevent or treat breast cancer.…”

The Microbiome in the Obesity-Breast Cancer Axis: Diagnostic and Therapeutic Potential

“…Studies have shown that the breast microbiome biomass decreases in breast cancer patients [77]. Additionally, distinct microbial communities have been observed in breast tissues of non-Hispanic Black and non-Hispanic White women, with differences in microbiome composition by race, breast cancer stage, or breast tumor subtype [24,78]. Dysbiosis of microbiota may contribute to obesity and obesity-related diseases through various mechanisms, including energy harvesting, direct effects on gene expression, and direct or indirect effects of chronic inflammation [79].…”