Cell type- and estrogen receptor-subtype specific regulation of selective estrogen receptor modulator regulatory elements

Ball, LJ; Levy, N; Zhao, XY; Griffin, C; Tagliaferri, M; Cohen, I; Ricke, WA; Speed, TP; Firestone, GL; Leitman, DC

Author(s): Ball, LJ; Levy, N; Zhao, XY; Griffin, C; Tagliaferri, M; Cohen, I; Ricke, WA; Speed, TP; Firestone, GL; Leitman, DC;
Details: Publication Year 2009-02-27,Volume 299,Issue #2,Page 204-211
Journal Title: MOLECULAR AND CELLULAR ENDOCRINOLOGY
Publication Type: Journal Article
Abstract: Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene can act as estrogen receptor (ER) antagonists or agonists depending on the cell type. The antagonistic action of tamoxifen has been invaluable for treating breast cancer, whereas the agonist activity of SERMs also has important clinical applications as demonstrated by the use of raloxifene for osteoporosis. Whereas the mechanism whereby SERMs function as antagonists has been studied extensively very little is known about how SERMs produce agonist effects in different tissues with the two ER types; ER alpha and ER beta. We examined the regulation of 32 SERM-responsive regions with ER alpha and ER beta in transiently transfected MCF-7 breast, Ishikawa endometrial, HeLa cervical and WAR-5 prostate cancer cells. The regions were regulated by tamoxifen and raloxifene in some cell types, but not in all cell lines. Tamoxifen activated similar number of regions with ER alpha and ERR in the cell lines, whereas raloxifene activated over twice as many regions with ER beta compared to ER alpha. In Ishikawa endometrial cancer cells, tamoxifen activated 17 regions with ER alpha, whereas raloxifene activated only 2 regions, which might explain their different effects on the endometrium. Microarray studies also found that raloxifene regulated fewer genes than tamoxifen in U2OS bone cancer cells expressing ER alpha, whereas tamoxifen was equally effective at regulating genes with ER alpha and ER beta. Our studies indicate that tamoxifen is a non-selective agonist, whereas raloxifene is a relative ER beta-selective agonist, and suggest that ER beta-selective SERMs might be safer for treating clinical conditions that are dependent on the agonist property of SERMs. (c) 2008 Elsevier Ireland Ltd. All rights reserved.
Publisher: ELSEVIER IRELAND LTD
Keywords: INVASIVE BREAST-CANCER; POSTMENOPAUSAL WOMEN; TISSUE-SPECIFICITY; NUCLEAR RECEPTORS; TAMOXIFEN; RALOXIFENE; BINDING; ALPHA; RISK; ACTIVATION
Publisher's Version: https://doi.org/10.1016/j.mce.2008.10.050
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2009-02-27 12:00:00