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or ERß in Human Osteosarcoma Cells: Distinct and Common Target Genes for These Receptors
Departments of Molecular and Integrative Physiology (F.S., J.F., B.S.K.) and Cell and Structural Biology (D.H.B., B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; and Women’s Health Research Institute (B.K., C.R.L.), 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}life.uiuc.edu.
Estrogens exert many important effects in bone, a tissue that contains both estrogen receptors 
and ß (ER and ERß). To compare the actions of these receptors, we generated U2OS human osteosarcoma cells stably expressing ER or ERß, at levels comparable with those in osteoblasts, and we characterized their response to 17ß-estradiol (E2) over time using Affymetrix GeneChip microarrays to determine the expression of approximately 12,000 genes, followed by quantitative PCR verification of the regulation of selected genes. Of the approximately 100 regulated genes we identified, some were stimulated by E2 equally through ER and ERß, whereas others were selectively stimulated via ER or ERß. The E2-regulated genes showed three distinct temporal patterns of expression over the 48-h time course studied. Of the functional categories of the E2-regulated genes, most numerous were those encoding cytokines and factors associated with immune response, signal transduction, and cell migration and cytoskeleton regulation, indicating that E2 can exert effects on multiple pathways in these osteoblast-like cell lines. Of note, E2 up-regulated several genes associated with cell motility selectively via ERß, in keeping with the selective E2 enhancement of the motility of ERß-containing cells. On genes regulated equally by E2 via ER or ERß, the phytoestrogen genistein preferentially stimulated gene expression via ERß. These studies indicate both common as well as distinct target genes for these two ERs, and identify many novel genes not previously known to be under estrogen regulation.
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