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BACKGROUND: Bile acids are generated and secreted by hepatocytes and are involved in intestinal circulation. Recently it has been reported that specific bile acids are accumulated in the breast cancer tumor microenvironment (TME), leading to a favorable prognosis for patients and reducing the aggressiveness and metastatic potential of the cancer. We hypothesized that breast cancers with increased bile acid metabolism may have a favorable clinical outcome due to the suppression of cancer cell proliferation. MATERIALS AND METHODS: We analyzed total of 6285 patients from three independent breast cancer cohorts with TCGA as an exploring cohort and METABRIC, GSE96058 as validation cohorts. We divided each cohort into "high" and "low" groups by the top and bottom quartiles of the score following the previous reports. RESULTS: High bile acid metabolism breast cancer enriched multiple metabolic pathway gene sets such as fatty acid and xenobiotic metabolism, as well as adipogenesis and protein secretion by gene set enrichment analysis (GSEA). Adipocytes and preadipocytes were significantly infiltrated in the high score group. Considering the possibility that activation of bile acid metabolism is due to accumulation of microbiome-derived bile acids in breast cancer, we identified that four microorganisms (Anaerococcus, Collimonas, Gammaretrovirus and Hymenobacter) significantly correlated with the bile acid metabolism using TCGA 16s RNA seq data. Surprisingly, protein secretion gene set was significantly enriched to tumors that are abundant in three out of four of these bacterial species. This may suggest that bile acid metabolism are elevated in response to bile acids secreted by the microbiome present in breast cancer TME. The bile acid metabolism was highest in ER+HER2- and lowest in triple-negative, the most aggressive form of breast cancer. The score was negatively correlated with Ki67 gene expression and histological grade, consistent with previous reports that breast cancers with high bile acid accumulation were less proliferative. In agreement, breast cancers with low bile acid metabolism was associated with significantly high silent and non-silent mutation rates, Intratumor Heterogeneity, Proliferation score and Homologous Recombination Defects, and enriched G2M checkpoint gene set. Finally, survival analysis showed that high bile acid metabolism group had significantly better disease free, disease specific and overall survival. CONCULUSIONS: Bile acid metabolism was associated with involvement of microbiome in TME, the suppression of cell proliferation, and better prognosis in breast cancer. Citation Format: Rongrong Wu, Quratulain Sabih, Masanori Oshi, Takashi Ishikawa, Li Yan, Kazuaki Takabe. Elevated bile acid metabolism is associated with breast cancer microbiome, less cell proliferation, and better survival [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 3061. |
