title: The major cyclic trimeric product of indole-3-carbinol is a strong agonist of the estrogen receptor signaling pathway.
abstract: Indole-3-carbinol (I3C), a component of Brassica vegetables, is under study as a preventive agent of cancers of the breast and other organs. Following ingestion, I3C is converted to a series of oligomeric products that presumably are responsible for the in vivo effects of I3C. We report the effects of the major trimeric product, 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b' ']triindole (CTr), on the estrogen receptor (ER) signaling pathways. Tumor-promoting effects of high doses of I3C may be due to activation of aryl hydrocarbon receptor (AhR)-mediated pathways; therefore, we also examined the effects of CTr on AhR activated processes. We observed that CTr is a strong agonist of ER function. CTr stimulated the proliferation of estrogen-responsive MCF-7 cells to a level similar to that produced by estradiol (E(2)) but did not affect the growth of the estrogen-independent cell line, MDA-MD-231. CTr displaced E(2) in competitive-binding studies and activated ER-binding to an estrogen responsive DNA element in gel mobility shift assays with EC(50)s of about 0.1 microM. CTr activated transcription of an E(2)-responsive endogenous gene and exogenous reporter genes in transfected MCF-7 cells, also with high potency. CTr failed to activate AhR-mediated pathways, consistent with the low-binding affinity of CTr for the AhR reported previously. Comparisons of the conformational characteristics of CTr with other ER ligands indicated a remarkable similarity with tamoxifen, a selective ER antagonist used as a breast cancer therapeutic agent and suggest an excellent fit of CTr into the ligand-binding site of the ER.
authors.affiliation: Division of Nutritional Sciences and Toxicology, and Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Riby
authors.forename: C
authors.initials: C
authors.lastname: Feng
authors.forename: Y C
authors.initials: YC
authors.lastname: Chang
authors.forename: C M
authors.initials: CM
authors.lastname: Schaldach
authors.forename: G L
authors.initials: GL
authors.lastname: Firestone
authors.forename: L F
authors.initials: LF
authors.lastname: Bjeldanes
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007211:Indoles / Q000819:agonists* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology; D011960:Receptors, Estrogen / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000737:chemistry; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D007211:Indoles; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene; C074140:5,6,11,12,17,18-hexahydrocyclononatriindole; C016517:indole-3-carbinol