ER ER ER ER - Endocrine Reviews

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