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(also known as estrogen response elements, <strong>ER</strong>Es) which are present in the promoter<br />
regions of target genes (classic action, figure 1A). In particular, the transcriptional<br />
activity of <strong>ER</strong> is enhanced by the binding of co-activators such as members of the p160<br />
family of nuclear-receptor co-activators [e.g. nuclear-receptor co-activator 1 (NCoA1 or<br />
SRC-1), NCoA2 (SRC-2), and NCoA3 (AIB1, SRC-3, TRAM1, RAC3, p/CIP or ACTR)<br />
(36, 37) (figure 1A)]. These proteins lead to the formation of large complexes that<br />
enhance <strong>ER</strong>-driven transcription by different mechanisms including recruitment of<br />
histone-acetyltransferases (HATs) that modulate the chromatin structure at the promoter<br />
site (36).<br />
In contrast to estrogens, estrogen antagonists induce a distinct receptor conformation<br />
leading to <strong>ER</strong> association with co-repressor complexes, such as nuclear-receptor co-<br />
repressor 1 (NCoR1) and NCoR2 (SMRT), rather than with co-activators, thereby<br />
shutting off gene transcription (38, 39) (figure 1A). Interestingly, selective estrogen<br />
receptor modulators (S<strong>ER</strong>Ms), including tamoxifen and raloxifene, have mixed<br />
agonist/antagonist activity, and may either stimulate or antagonize <strong>ER</strong> function<br />
depending on the tissue, cell, and gene context (40).<br />
Many co-regulatory proteins may be present at rate-limiting levels in the nucleus, so that<br />
changes in their level of expression and/or activity can lead to alterations of <strong>ER</strong> signaling.<br />
In particular, overexpression of co-activators and downregulation of co-repressors can<br />
negate the inhibitory effects of endocrine therapy, especially in the case of S<strong>ER</strong>Ms (41-<br />
45). In this regard, recent studies have observed that high AIB1 expression in patients<br />
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