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Estrogen Receptors and β as Determinants of Gene Expression: Influence of Ligand, Dose, and Chromatin Binding

Departments of Molecular and Integrative Physiology (E.C.C., S.-H.P., B.S.K.), Cell and Developmental Biology (B.S.K.), Food Science and Human Nutrition (W.G.H.), and Chemistry and Bioengineering (T.H.C., J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; and Women’s Health and Musculoskeletal Biology (B.K.), Wyeth Research, Collegeville, Pennsylvania 19426

Address all correspondence and requests for reprints to: Dr. Benita S. Katzenellenbogen, University of Illinois, Department of Molecular and Integrative Physiology, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801-3704. E-mail: katzenel{at}uiuc.edu.

Estrogen receptors and β (ER and ERβ) mediate the actions of estrogens in a variety of normal and cancer target cells. Estrogens differ in their preference for these ERs, and many phytoestrogens bind preferentially to ERβ. To investigate how phytoestrogens such as genistein impact ER-regulated gene expression, we used adenoviral gene delivery of ERβ coupled with ER depletion with small interfering RNA to generate human breast cancer (MCF-7) cells expressing four complements of ER and ERβ. We examined the dose-dependent effects of genistein on genome-wide gene expression by DNA microarrays and monitored the recruitment of ERs and coregulators to responsive regions of estrogen-regulated genes. At a low (6 nM) concentration, genistein regulated gene expression much more effectively in cells coexpressing ER and ERβ than in cells expressing ER alone, whereas at high concentration (300 nM), genistein induced transcriptome changes very similar to that of 17β-estradiol. We demonstrate that ERβ is preferentially activated by genistein and is recruited to estrogen-responsive genomic sites and that differential occupancy of ER and ERβ by genistein and 17β-estradiol in turn influences the recruitment patterns of coregulators such as steroid receptor coactivator 3 (SRC3) and receptor-interacting protein 140 (RIP140). Our observations indicate that genistein is a potency-selective ligand for gene expression regulation by ER and ERβ and that the ability of ER and ERβ to serve as determinants of gene expression is greatly influenced by the nature of the ligand, by ligand dose, and by the differential abilities of ligand-ER complexes to recruit different coregulators at ER binding sites of hormone-regulated genes.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Coregulators:   RIP140  |  AIB1

Ligands:   17β-Estradiol  |  Fulvestrant