Identification of Bacterial Metabolites Modulating Breast Cancer Cell Proliferation and Epithelial-Mesenchymal Transition

Breast cancer patients are characterized by the oncobiotic transformation of multiple microbiome communities, including the gut microbiome. Oncobiotic transformation of the gut microbiome impairs the production of antineoplastic bacterial metabolites. The goal of this study was to identify bacterial metabolites with antineoplastic properties. We constructed a 30-member bacterial metabolite library and screened the library compounds for effects on cell proliferation and epithelial-mesenchymal transition. The metabolites were applied to 4T1 murine breast cancer cells in concentrations corresponding to the reference serum concentrations. However, yric acid, glycolic acid, d-mannitol, 2,3-butanediol, and trans-ferulic acid exerted cytostatic effects, and 3-hydroxyphenylacetic acid, 4-hydroxybenzoic acid, and vanillic acid exerted hyperproliferative effects. Furthermore, 3-hydroxyphenylacetic acid, 4-hydroxybenzoic acid, 2,3-butanediol, and hydrocinnamic acid inhibited epithelial-to-mesenchymal (EMT) transition. We identified redox sets among the metabolites (d-mannitol-d-mannose, 1-butanol-butyric acid, ethylene glycol-glycolic acid-oxalic acid), wherein only one partner within the set (d-mannitol, butyric acid, glycolic acid) possessed bioactivity in our system, suggesting that changes to the local redox potential may affect the bacterial secretome. Of the nine bioactive metabolites, 2,3-butanediol was the only compound with both cytostatic and anti-EMT properties.

Automated summary

Breast cancer patients experience changes in their gut microbiome, leading to impaired production of antineoplastic bacterial metabolites. This study aimed to identify bacterial metabolites with antineoplastic properties. A library of 30 bacterial metabolites was screened for their effects on cell proliferation and epithelial-mesenchymal transition in breast cancer cells. Several metabolites exhibited cytostatic or hyperproliferative effects, and some inhibited epithelial-to-mesenchymal transition. Redox sets of metabolites were identified, with only one partner in the set possessing bioactivity, suggesting a potential role of local redox potential in the bacterial secretome. Among the bioactive metabolites, only 2,3-butanediol had both cytostatic and anti-EMT properties.