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
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.