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A more recent version of this article appeared on March 1, 2004
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Submitted on June 4, 2003
Revised on November 7, 2003
Accepted on November 19, 2003
and 
1 From the Department of Obstetrics, Gynecology and Reproductive Sciences, Cellular and Molecular Pharmacology, Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143-0556
2 Cellular and Molecular Pharmacology, Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143-0556
3 GeneTex, Inc., San Antonio, TX 78245
4 From the Department of Obstetrics, Gynecology and Reproductive Sciences, Cellular and Molecular Pharmacology, Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143-0556, Dale C. Leitman, University of California San Francisco, HSE 1619, Center for Reproductive Sciences, 513 Parnassus Avenue, San Francisco, CA 94143-0556
* Corresponding author. E-mail address: leitmand{at}obgyn.ucsf.edu.
Estrogens and selective estrogen receptor modulators (SERMs) interact with estrogen receptor (ER) ER
and ER
to activate or repress gene transcription. To understand how estrogens and SERMs exert tissue-specific effects, we performed microarray analysis to determine if ER or ER regulate different target genes in response to estrogens and SERMs. We prepared human U2OS osteosarcoma cells that are stably transfected with a tetracycline-inducible vector to express ER or ER. Western blotting, immunohistochemistry and immunoprecipitation studies confirmed that U2OS-ER cells synthesized only ER, and that U2OS-ER cells expressed exclusively ER. U2OS-ER and U2OS-ER cells were treated either with 17-estradiol (E2), raloxifene, and tamoxifen for 18 h. Labeled cRNAs were hybridized with Affymetrix U95Av2 GeneChips. A total of 228, 190 and 236 genes were significantly activated or repressed at least 1.74-fold in U2OS-ER and U2OS-ER cells by E2, raloxifene and tamoxifen, respectively. Most genes regulated in ER cells in response to E2, raloxifene and tamoxifen were distinct from those regulated by ER cells. Only 38 of the 228 (17%) genes were regulated by E2 in both U2OS-ER and U2OS-ER cells. Raloxifene and tamoxifen regulated only 27% of the same genes in both the ER and ER cells. A subset of genes involved in bone-related activities regulated by E2, raloxifene and tamoxifen were also distinct. Our results demonstrate that most genes regulated by ER are distinct from those regulated by ER in response to E2 and SERMs. These results indicate that estrogens and SERMs exert tissue-specific effects by regulating unique sets of targets genes through ER and ER.
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