Decreased bile acid metabolism and association with prognosis reflecting microbiome in tumor microenvironment involved in cancer cell proliferation in breast cancer.

Authors

null

Rongrong Wu

Roswell Park Comprehensive Cancer Center, Buffalo, NY

Rongrong Wu , Irene Yu , Yoshihisa Tokumaru , Mariko Asaoka , Masanori Oshi , Takashi Ishikawa , Kazuaki Takabe

Organizations

Roswell Park Comprehensive Cancer Center, Buffalo, NY, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, Department of Breast Surgical Oncology, Tokyo Medical University, Tokyo, Japan

Research Funding

No funding received

Background: Bile acids are metabolized by the gut microbiome and are involved in fat absorption. Contrary to their carcinogenic role in gastrointestinal cancers, bile acids have been reported to inhibit cancer cell proliferation in breast cancer. We hypothesized that activation of bile acid metabolism is associated with a better prognosis based on previous reports regarding the antitumor effects of bile acids in breast cancer cells. Methods: A total of 6050 patients from three large open primary breast cancer cohorts (GSE96058, METABRIC, and TCGA) were analyzed by bile acid metabolism scores calculated by gene set variation analysis, and the association with the microbiome of the breast cancer tumor microenvironment in TCGA was also investigated. Results: We found that disease free, disease specific and overall survival was significantly improved in the high bile acid metabolism group, which was validated by three large breast cancer cohorts. However, apoptosis, ROS, and unfolded protein response gene sets were not found to be enriched in the high bile acid metabolism group, despite the expectation that oxidative stress-induced apoptosis would lead to improved survival. Several metabolic pathways and pathways associated with bile acid production and regulation were enriched in this group. On the other hand, Ki67 and nuclear grade were higher, and several cell proliferation-related gene sets were upregulated in the low bile acid metabolism group, especially the G2M checkpoint in all cohorts. In association with the higher cell proliferation, the low bile acid metabolism group showed higher mutation load, immune activation, and infiltration of anti-cancer immune cells. We further investigated that the composition of the microbiome in each group and four species that demonstrated significant abundance in the high bile acid metabolism group and three species in the low bile acid metabolism group. Surprisingly, almost all the cell proliferation-related gene sets from Hallmark were enriched in the three microorganisms-rich groups specific for low bile acid metabolism breast cancer. This was not the case for the microorganisms specific to high bile acid metabolism. Conclusions: Clinical relevance of bile acid metabolism in breast cancer is that low bile acid metabolism with abundant Lactobacillus, Ruegeria, and Marichromatium is associated with highly proliferative cancer and worse survival, rather than the growth suppression effect of bile acids.

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Abstract Details

Meeting

2022 ASCO Annual Meeting

Session Type

Publication Only

Session Title

Breast Cancer—Local/Regional/Adjuvant

Track

Breast Cancer

Sub Track

Biologic Correlates

Citation

J Clin Oncol 40, 2022 (suppl 16; abstr e12539)

DOI

10.1200/JCO.2022.40.16_suppl.e12539

Abstract #

e12539

Abstract Disclosures

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