Tamoxifen resistant breast cancer: coregulators determine the direction oftranscription by antagonist-occupied steroid receptors

Citation
Gs. Takimoto et al., Tamoxifen resistant breast cancer: coregulators determine the direction oftranscription by antagonist-occupied steroid receptors, J STEROID B, 69(1-6), 1999, pp. 45-50
Citations number
28
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
ISSN journal
09600760 → ACNP
Volume
69
Issue
1-6
Year of publication
1999
Pages
45 - 50
Database
ISI
SICI code
0960-0760(199904/06)69:1-6<45:TRBCCD>2.0.ZU;2-G
Abstract
Pharmacological antagonists of steroid receptor action had been thought to exert their effects by a passive mechanism driven principally by the abilit y of the antagonist to compete with agonist for the ligand binding site. Ho wever, recent analyses of antagonist-occupied receptor function suggest a m ore complex picture. Antagonists can be subdivided into two groups, type I: or pure antagonists, and type II, or mixed antagonists that can have varia ble transcriptional activity based upon differential dimerization and DNA b inding properties. This led us to propose that receptor antagonism may not simply be a passive competition for the ligand binding site, but may, in so me cases, involve active recruitment of corepressor or coactivator proteins to produce a mixed transcriptional phenotype. We used a yeast two-hybrid s creen to identify proteins that interact specifically with antagonist-occup ied receptors. Two proteins have been characterized: L7/SPA, a ribosome-ass ociated protein that is localized in both the cytoplasm and nucleus, bur wi th no known extranucleolar nuclear function and hN-CoR, the human homolog o f the mouse thyroid receptor corepressor mN-CoR. In in vivo transcription a ssays we show that L7/SPA enhances the partial agonist activity of type II mixed antagonists, and that N-CoR and the related corepressor, SMRT, suppre sses it. The coregulators do not affect agonists or pure antagonists, Moreo ver, the net agonist activity seen with mixed antagonists is a function of the ratio of coactivator to corepressor. Based upon these results, we propo sed that in breast tumors the inappropriate agonist activity seen with ther apeutic antagonists such as tamoxifen is responsible for the hormone-resist ant state. To confirm this, we are quantitating coactivator/corepressor rat ios in breast tumor cells lines and clinical breast cancers. Results should provide new insights into the mechanisms underlying the progression of bre ast cancer to hormone resistance, and may suggest strategies for delaying o r reversing this process. (C) 1999 Elsevier Science Ltd. All rights reserve d.