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
mu M), 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 (7 alpha/beta-hydroxysteroid dehydroxylase,
the key enzyme in LCA generation) gene in fecal DNA, all suggesting reduced microbial
generation of LCA in early breast cancer.
