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Estrogen Receptor and ß Heterodimers Exert Unique Effects on Estrogen- and Tamoxifen-Dependent Gene Expression in Human U2OS Osteosarcoma Cells

Department of Biochemistry and Molecular Biology (D.G.M., F.J.S., M.S., B.J.G., T.C.S.), and Endocrine Research Unit (S.K.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: David G. Monroe, Ph.D., Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 1601C Guggenheim, 200 1st Street Southwest, Rochester, Minnesota 55905. E-mail: Monroe.David{at}mayo.edu.

The 17ß-estradiol (E2) receptor isoforms [estrogen receptor (ER) and ERß] bind E2 and selective ER modulators (SERMs) as homodimers (/ or ß/ß) or heterodimers (/ß) to regulate gene expression. Although recent studies have shown that ER homodimers regulate unique sets of E2-responsive genes, little information exists regarding the transcriptional actions of the ER/ß heterodimer. This paper describes the development of a U2OS human osteosarcoma (osteoblast) cell line stably expressing both ER and ERß isoforms at a ratio of 1:4, a ratio reported to exist in normal, mature osteoblast cells derived from cancellous bone. The regulation of endogenous genes by E2 and 4-hydroxy-tamoxifen were measured in these cells using gene microarrays and real-time RT-PCR. Both E2 and 4-hydroxy-tamoxifen were shown to regulate unique sets of endogenous genes in the U2OS-ER/ß heterodimer cell line (20% and 27% of total, respectively), compared with all the genes regulated in U2OS-ER homodimer cell lines. Furthermore, two novel E2-regulated genes, retinoblastoma binding protein 1 and 7-dehydrocholesterol reductase, were found to contain estrogen response element-like sequences that directly bind the ER/ß heterodimer. These results suggest that the expression of both ER isoforms, forming functional ER/ß heterodimers, result in unique patterns of gene regulation, many of which are distinct from the genes regulated by the ER homodimers.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen

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