title: Genistein disrupts glucocorticoid receptor signaling in human uterine endometrial Ishikawa cells.
abstract: BACKGROUND
  The link between environmental estrogen exposure and defects in the female reproductive tract is well established. The phytoestrogen genistein is able to modulate uterine estrogen receptor (ER) activity, and dietary exposure is associated with uterine pathologies. Regulation of stress and immune functions by the glucocorticoid receptor (GR) is also an integral part of maintaining reproductive tract function; disruption of GR signaling by genistein may also have a role in the adverse effects of genistein.
  
  
  OBJECTIVE
  We evaluated the transcriptional response to genistein in Ishikawa cells and investigated the effects of genistein on GR-mediated target genes.
  
  
  METHODS
  We used Ishikawa cells as a model system to identify novel targets of genistein and the synthetic glucocorticoid dexamethasone through whole genome microarray analysis. Common gene targets were defined and response patterns verified by quantitative real-time reverse-transcription polymerase chain reaction. The mechanism of transcriptional antagonism was determined for select genes.
  
  
  RESULTS
  Genistein regulated numerous genes in Ishikawa cells independently of estradiol, and the response to coadministration of genistein and dexamethasone was unique compared with the response to either estradiol or dexamethasone alone. Furthermore, genistein altered glucocorticoid regulation of GR target genes. In a select set of genes, co-regulation by dexamethasone and genistein was found to require both GR and ERα signaling, respectively.
  
  
  CONCLUSIONS
  Using Ishikawa cells, we observed that exposure to genistein resulted in distinct changes in gene expression and unique differences in the GR transcriptome.
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Whirledge
authors.forename: Linda T
authors.initials: LT
authors.lastname: Senbanjo
authors.forename: John A
authors.initials: JA
authors.lastname: Cidlowski
mesh_terms: D045744:Cell Line, Tumor; D003907:Dexamethasone; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D046228:Microarray Analysis; D048789:Phytoestrogens / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D048789:Phytoestrogens; D011965:Receptors, Glucocorticoid; D004958:Estradiol; D003907:Dexamethasone; D019833:Genistein