Abstract 3022: Tryptophan metabolism is associated with obesity and triple negative breast cancer risk in black and white women

Abstract

Non-Hispanic black (NHB) women are more likely to be diagnosed and die from triple negative breast cancer (TNBC) than non-Hispanic white (NHW) women. We previously showed that TNBC tissues display a distinct microbial signature. Obesity which contributes to chronic low-grade inflammation and gut microbial dysbiosis further exacerbates TNBC outcomes for NHB women. However, it is unclear the extent to which microbial differences in breast tumor tissues may be driven by alterations in microbial metabolites as a result of obesity status. Therefore, the aim of this global metabolomic profiling study was to investigate alterations in microbial metabolism pathways in breast tissues of NHB and NHW obese women (avg. BMI = 35.7) relative to non-obese women (avg. BMI = 23.4) with and without TNBC. In this study, we analyzed 984 metabolites derived from a total of 51 NHB and NHW women, including 15 patients with TNBC, 12 patients with less aggressive Luminal A-type breast cancer, and 24 healthy controls for comparison using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to identify microbial metabolites and metabolomic signatures that differ by breast tumor subtype and obesity status. We detected 501 significantly increased metabolites and 33 significantly decreased metabolites in TNBC patients compared to controls. Principal component analysis and hierarchical clustering of the global metabolite profiling data revealed separation between the metabolic signatures of normal and breast tumor tissue. Random forest analysis revealed a unique biochemical signature associated with elevated L-Tryptophan (Trp) and Kynurenine (Kyn) metabolites and lower levels of microbial-derived metabolites critical for controlling inflammation and immune response in obese individuals and those with TNBC. TCGA analysis further revealed that expression of key Trp enzymes was significantly associated with worse survival outcomes in TNBC patients compared to other breast tumor subtypes. Our findings highlight a potential role for Trp metabolism through the Kyn pathway in obesity and TNBC risk. Further investigations into the Kyn metabolomic pathway may prove to be a novel therapeutic target for TNBC. Citation Format: Alana Smith, Qingqing Gu, Ernestine Kubi Amos-Abanyie, Elizabeth Tolley, Lu Lu, Beverly Lyn-Cook, Athena Starlard-Davenport. Tryptophan metabolism is associated with obesity and triple negative breast cancer risk in black and white women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3022.

The microbiome: a link between obesity and breast cancer risk

“…Random forest analysis showed a unique biochemical signature associated with elevated L-Tryptophan and Kynurenine metabolites and lower levels of microbial-derived metabolites critical for controlling inflammation and immune response in obese individuals and those with TNBC. Additionally, analysis of The Cancer Genome Atlas revealed that the expression of key Lenzymes was significantly associated with worse survival outcomes in TNBC patients (Smith et al, 2022). Overall, these findings suggest a complex interplay between bacterial metabolism, tryptophan derivatives, obesity, and breast cancer development and progression.…”

“…Tryptophan metabolism has also been associated with obesity and TNBC. (Smith A, et al, 2022) investigated alterations in microbial metabolism pathways in breast tissues of obese women relative to non-obese women with and without TNBC. Random forest analysis showed a unique biochemical signature associated with elevated L-Tryptophan and Kynurenine metabolites and lower levels of microbial-derived metabolites critical for controlling inflammation and immune response in obese individuals and those with TNBC.…”