Abstract
Glyceollins, a group of novel phytoalexins isolated from activated soy, have recently been demonstrated to be novel antiestrogens that bind to the estrogen receptor (ER) and inhibit estrogen-induced tumor progression. Our previous publications have focused specifically on inhibition of tumor formation and growth by the glyceollin mixture, which contains three glyceollin isomers (I, II, and III). Here, we show the glyceollin mixture is also effective as a potential antiestrogenic, therapeutic agent that prevents estrogen-stimulated tumorigenesis and displays a differential pattern of gene expression from tamoxifen. By isolating the individual glyceollin isomers (I, II, and III), we have identified the active antiestrogenic component by using competition binding assays with human ERα and in an estrogen-responsive element-based luciferase reporter assay. We identified glyceollin I as the active component of the combined glyceollin mixture. Ligand-receptor modeling (docking) of glyceollin I, II, and III within the ERα ligand binding cavity demonstrates a unique type II antiestrogenic confirmation adopted by glyceollin I but not isomers II and III. We further compared the effects of glyceollin I to the antiestrogens, 4-hydroxytamoxifen and ICI 182,780 (fulvestrant), in MCF-7 breast cancer cells and BG-1 ovarian cancer cells on 17β-estradiol-stimulated expression of progesterone receptor and stromal derived factor-1α. Our results establish a novel inhibition of ER-mediated gene expression and cell proliferation/survival. Glyceollin I may represent an important component of a phytoalexin-enriched food (activated) diet in terms of chemoprevention as well as a novel therapeutic agent for hormone-dependent tumors.
Footnotes
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This work was supported by a cooperative agreement with the U.S. Department of Agriculture [Grants 58-6435-7-019, 58-6435-7-019]; the United States Department of Defense Breast Cancer Research Program [Grants DAMD17-01-1-0655, DAMD17-01-1-0655 ]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK059389]; The Tulane/Xavier Center for Bioenvironmental Research; and the National Institutes of Health National Heart, Lung, and Blood Institute [Grant T32-HL00797305] (Training Grant in Lung Molecular and Cell Pathobiology).
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M.C.Z. and S.L.T. share co-first authorship.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.160382
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ABBREVIATIONS:
- ER
- estrogen receptor(s)
- ICI 182,780
- fulvestrant
- HPLC
- high-performance liquid chromatography
- DMEM
- Dulbecco's modified Eagle's medium
- 4-OH-tamoxifen
- 4-hydroxytamoxifen
- FBS
- fetal bovine serum
- PBS
- phosphate-buffered saline
- CS
- charcoal-stripped
- Con
- control
- E2
- 17β-estradiol
- Gly
- glyceollin mixture
- DMSO
- dimethyl sulfoxide
- RT
- reverse transcription
- PRC
- polymerase chain reaction
- SDF-1
- stromal cell-derived factor-1
- PgR
- progesterone receptor
- Ct
- fractional cycle number
- ES2
- fluorescent ligand
- RBA
- relative binding affinity(ies)
- NGFR
- nerve growth factor receptor
- ERE
- estrogen-responsive element.
- Received August 17, 2009.
- Accepted September 30, 2009.
- © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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