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Indole-3-Carbinol Selectively Uncouples Expression and Activity of Estrogen Receptor Subtypes in Human Breast Cancer Cells

Department of Molecular and Cell Biology and the Cancer Research Laboratory (S.N.S., V.K., C.N.E., V.B.D., G.L.F.), and Department of Nutritional Sciences and Toxicology (L.F.B.), University of California at Berkeley, Berkeley, California 94720-3200

Address all correspondence and requests for reprints to: Gary L. Firestone, Department of Molecular and Cell Biology, 591 LSA, University of California at Berkeley, Berkeley, California 94720-3200. E-mail: glfire{at}berkeley.edu.

Estrogen-responsive breast cancer cells, such as MCF7 and T47D cells, express both estrogen receptor (ER)- (ER) and ERß. Indole-3-carbinol (I3C) strongly down-regulated ER protein and transcript levels, without altering the level of ERß protein, in both cell lines. In cells transfected with the ER promoter linked to a luciferase gene reporter, I3C ablated ER promoter activity. Propyl pyrazole triol (PPT) is a highly selective ER agonist, whereas, 17ß-estradiol activates both ER and ERß. I3C treatment inhibited the PPT- and 17ß-estradiol-induced proliferation of breast cancer cells, disrupted the PPT and 17ß-estradiol stimulation of estrogen response element (ERE)-driven reporter plasmid activity as well as of endogenous progesterone receptor transcripts. Using an in vitro ERE binding assay, I3C was shown to inhibit the level of functional ER and stimulated the level of ERE binding ERß even though the protein levels of this receptor remained constant. In ER–/ERß+ MDA-MB-231 breast cancer cells, I3C treatment stimulated a 6-fold increase in binding of ERß to the ERE. I3C also induced ERE- and activator protein 1-driven reporter plasmid activities in the absence of an ER agonist, suggesting that ERß is activated in indole-treated cells. Taken together, our results demonstrate that the expression and function of ER and ERß can be uncoupled by I3C with a key cellular consequence being a significantly higher ERß:ER ratio that is generally highly associated with antiproliferative status of human breast cancer cells.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol