title: Glyceollin I enantiomers distinctly regulate ER-mediated gene expression.
abstract: Glyceollins are pterocarpan phytoalexins elicited in high concentrations when soybeans are stressed. We have previously reported that the three glyceollin isomers (GLY I-III) exhibit antiestrogenic properties, which may have significant biological effects upon human exposure. Of the three isomers, we have recently shown that glyceollin I is the most potent antiestrogen. Natural (-)-glyceollin I recently was synthesized along with its racemate and unnatural (+) enantiomer. In this study, we compared the glyceollin I enantiomers' ER binding affinity, ability to inhibit estrogen responsive element transcriptional (ERE) activity and endogenous gene expression in MCF-7 cells. The results demonstrated similar binding affinities for both ERalpha and ERbeta. Reporter gene assays in MCF-7 cells revealed that while (+)-glyceollin I slightly stimulated ERE transcriptional activity, (-)-glyceollin I decreased activity induced by estrogen. Co-transfection reporter assays performed in HEK 293 cells demonstrated that (+)-glyceollin I increased ERE transcriptional activity of ERalpha and ERbeta with and without estrogen with no antiestrogenic activity observed. Conversely, (-)-glyceollin I decreased the activity of both ER subtypes stimulated by estradiol demonstrating potent antiestrogenic properties. Additionally, each Gly I enantiomer induced unique gene expression profiles in a PCR array panel of genes commonly altered in breast cancer.
authors.affiliation: Tulane Department of Medicine, Section of Hematology & Medical Oncology, Tulane University Health Science Center, New Orleans, LA 70112, USA.
authors.forename: Florastina
authors.initials: F
authors.lastname: Payton-Stewart
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Khupse
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Boué
authors.forename: Steven
authors.initials: S
authors.lastname: Elliott
authors.forename: M Carla
authors.initials: MC
authors.lastname: Zimmermann
authors.forename: Elena V
authors.initials: EV
authors.lastname: Skripnikova
authors.forename: Hasina
authors.initials: H
authors.lastname: Ashe
authors.forename: Syreeta L
authors.initials: SL
authors.lastname: Tilghman
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Beckman
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Cleveland
authors.forename: John A
authors.initials: JA
authors.lastname: McLachlan
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhatnagar
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wiese
authors.forename: Paul
authors.initials: P
authors.lastname: Erhardt
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
mesh_terms: D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D036343:Pterocarpans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020218:Response Elements / Q000235:genetics; D013237:Stereoisomerism; D013379:Substrate Specificity; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D036343:Pterocarpans; C017343:glyceollin