TY - JOUR
T1 - Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness
AU - Mikó, Edit
AU - Vida, András
AU - Kovács, Tünde
AU - Ujlaki, Gyula
AU - Trencsényi, György
AU - Márton, Judit
AU - Sári, Zsanett
AU - Kovács, Patrik
AU - Boratkó, Anita
AU - Hujber, Zoltán
AU - Csonka, Tamás
AU - Antal-Szalmás, Péter
AU - Watanabe, Mitsuhiro
AU - Gombos, Imre
AU - Csoka, Balazs
AU - Kiss, Borbála
AU - Vígh, László
AU - Szabó, Judit
AU - Méhes, Gábor
AU - Sebestyén, Anna
AU - Goedert, James J.
AU - Bai, Péter
N1 - Funding Information:
Our work was supported by grants from NKFIH ( K123975 , PD116262 , PD124110 , GINOP-2.3.2-15-2016-00006 , GINOP-2.3.3-15-2016-00021 ), the Momentum fellowship of the Hungarian Academy of Sciences and the University of Debrecen and a Bolyai fellowship to GT, AS and AB. This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health ( Z01CP010214 ).
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Endothelial-mesenchymal transition
KW - Lithocholic acid
KW - Microbiome
KW - OXPHOS
KW - TGR5
UR - http://www.scopus.com/inward/record.url?scp=85046624546&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046624546&partnerID=8YFLogxK
U2 - 10.1016/j.bbabio.2018.04.002
DO - 10.1016/j.bbabio.2018.04.002
M3 - Article
C2 - 29655782
AN - SCOPUS:85046624546
VL - 1859
SP - 958
EP - 974
JO - Biochimica et Biophysica Acta - Bioenergetics
JF - Biochimica et Biophysica Acta - Bioenergetics
SN - 0005-2728
IS - 9
ER -