Farnesoid X receptor, through the binding with steroidogenic factor 1-responsive element, inhibits aromatase expression in tumor Leydig cells.

Abstract	The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that regulates bile acid homeostasis. It is expressed in the liver and the gastrointestinal tract, but also in several non-enterohepatic tissues including testis. Recently, FXR was identified as a negative modulator of the androgen-estrogen-converting aromatase enzyme in human breast cancer cells. In the present study we detected the expression of FXR in Leydig normal and tumor cell lines and in rat testes tissue. We found, in rat Leydig tumor cells, R2C, that FXR activation by the primary bile acid chenodeoxycholic acid (CDCA) or a synthetic agonist GW4064, through a SHP-independent mechanism, down-regulates aromatase expression in terms of mRNA, protein levels, and its enzymatic activity. Transient transfection experiments, using vector containing rat aromatase promoter PII, evidenced that CDCA reduces basal aromatase promoter activity. Mutagenesis studies, electrophoretic mobility shift, and chromatin immunoprecipitation analysis reveal that FXR is able to compete with steroidogenic factor 1 in binding to a common sequence present in the aromatase promoter region interfering negatively with its activity. Finally, the FXR-mediated anti-proliferative effects exerted by CDCA on tumor Leydig cells are at least in part due to an inhibition of estrogen-dependent cell growth. In conclusion our findings identify for the first time the activators of FXR as negative modulators of the aromatase enzyme in Leydig tumor cell lines.
Authors	Stefania Catalano, Rocco Malivindi, Cinzia Giordano, Guowei Gu, Salvatore Panza, Daniela Bonofiglio, Marilena Lanzino, Diego Sisci, Maria Luisa Panno, Sebastiano Andò
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 8 Pg. 5581-93 (Feb 19 2010) ISSN: 1083-351X [Electronic] United States
PMID	20026603 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Cathartics Isoxazoles NR5A1 protein, human Neoplasm Proteins Receptors, Cytoplasmic and Nuclear Steroidogenic Factor 1 nuclear receptor subfamily 0, group B, member 2 steroidogenic factor 1, mouse steroidogenic factor 1, rat farnesoid X-activated receptor Chenodeoxycholic Acid Aromatase GW 4064
Topics	Animals Aromatase (biosynthesis, genetics) Cathartics (pharmacology) Chenodeoxycholic Acid (pharmacology) Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic HeLa Cells Hep G2 Cells Humans Isoxazoles (pharmacology) Leydig Cell Tumor (genetics, metabolism, pathology) Leydig Cells (metabolism, pathology) Male Mice Neoplasm Proteins (genetics, metabolism) Rats Rats, Inbred F344 Receptors, Cytoplasmic and Nuclear (genetics, metabolism) Response Elements Steroidogenic Factor 1 (genetics, metabolism)

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