title: Genistein effects on stromal cells determines epithelial proliferation in endometrial co-cultures.
abstract: BACKGROUND
  Estrogen is the leading etiologic factor for endometrial cancer. Estrogen-induced proliferation of endometrial epithelial cells normally requires paracrine growth factors produced by stromal cells. Epidemiologic evidence indicates that dietary soy prevents endometrial cancer, and implicates the phytoestrogen genistein in this effect. However, results from previous studies are conflicting regarding the effects of genistein on hormone responsive cancers.
  
  
  METHODS
  The effects of estrogen and genistein on proliferation of Ishikawa (IK) endometrial adenocarcinoma cells were examined in co-cultures of IK cells with endometrial stromal cells, recapitulating the heterotypic cell-to-cell interactions observed in vivo. The roles of estrogen receptor (ER)α and ERβ were evaluated using ERα and ERβ specific agonists. ER activation and cell proliferation in the IK epithelial cells were determined by alkaline phosphatase assay and Coulter counter enumeration, respectively.
  
  
  RESULTS
  Both estrogen and genistein increased estrogen receptor-induced gene activity in IK cells over a range of concentrations. Estrogen alone but not genistein increased IK proliferation in co-cultures. When primed by estrogen treatment, increasing concentrations of genistein produced a biphasic effect on IK proliferation: nM concentrations inhibited estrogen-induced proliferation while μM concentrations increased proliferation. Studies with an ERβ-specific agonist produced similar results. Genistein did not influence the effects of estrogen on IK proliferation in monoculture.
  
  
  CONCLUSIONS
  Our study indicates that nutritionally relevant concentrations (nM) of genistein inhibit the proliferative effects of estrogen on endometrial adenocarcinoma cells presumably through activation of stromal cell ERβ. We believe that sub-micromolar concentrations of genistein may represent a novel adjuvant for endometrial cancer treatment and prevention.
authors.affiliation: Department of Pathology and Laboratory Medicine, 620 Brinkhous-Bullitt Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525, USA.
authors.forename: Brante P
authors.initials: BP
authors.lastname: Sampey
authors.forename: Terrence D
authors.initials: TD
authors.lastname: Lewis
authors.forename: Claire S
authors.initials: CS
authors.lastname: Barbier
authors.forename: Liza
authors.initials: L
authors.lastname: Makowski
authors.forename: David G
authors.initials: DG
authors.lastname: Kaufman
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002450:Cell Communication; D049109:Cell Proliferation / Q000187:drug effects*; D018920:Coculture Techniques; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D017154:Stromal Cells / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D019833:Genistein; D000469:Alkaline Phosphatase