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Biochim Biophys Acta Bioenerg. 2018 Sep;1859(9):958-974. doi: 10.1016/j.bbabio.2018.04.002. Epub 2018 Apr 13.

Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness.

Author information

1
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Hungary; MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen 4032, Hungary.
2
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Hungary.
3
Department of Medical Imaging, Faculty of Medicine, University of Debrecen, 4032, Hungary.
4
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, 1085, Hungary.
5
Department of Pathology, Faculty of Medicine, University of Debrecen, 4032, Hungary.
6
Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032, Hungary.
7
Department of Internal Medicine, School of Medicine, Keio University Endo, Fujisawa-shi, Kanagawa 252-0882, Japan.
8
Biological Research Center, 6701 Szeged, Hungary.
9
Deptartment of Anesthesiology, Columbia University Medical Center, New York, NY 10032, USA.
10
Department of Dermatology, Faculty of Medicine, University of Debrecen, 4032, Hungary.
11
Department of Microbiology, Faculty of Medicine, University of Debrecen, 4032, Hungary.
12
National Cancer Institute, National Institutes of Health, Bethesda, 20982, MD, USA.
13
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Hungary; Department of Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032, Hungary; MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen 4032, Hungary. Electronic address: baip@med.unideb.hu.

Abstract

Our study aimed at finding a mechanistic relationship between the gut microbiome and breast cancer. Breast cancer cells are not in direct contact with these microbes, but disease could be influenced by bacterial metabolites including secondary bile acids that are exclusively synthesized by the microbiome and known to enter the human circulation. In murine and bench experiments, a secondary bile acid, lithocholic acid (LCA) in concentrations corresponding to its tissue reference concentrations (< 1 μM), reduced cancer cell proliferation (by 10-20%) and VEGF production (by 37%), aggressiveness and metastatic potential of primary tumors through inducing mesenchymal-to-epithelial transition, increased antitumor immune response, OXPHOS and the TCA cycle. Part of these effects was due to activation of TGR5 by LCA. Early stage breast cancer patients, versus control women, had reduced serum LCA levels, reduced chenodeoxycholic acid to LCA ratio, and reduced abundance of the baiH (7α/β-hydroxysteroid dehydroxylase, the key enzyme in LCA generation) gene in fecal DNA, all suggesting reduced microbial generation of LCA in early breast cancer.

KEYWORDS:

Breast cancer; Endothelial-mesenchymal transition; Lithocholic acid; Microbiome; OXPHOS; TGR5

PMID:
29655782
DOI:
10.1016/j.bbabio.2018.04.002
[Indexed for MEDLINE]

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