Physiol Rev 87: 905–931, 2007;
doi:10.1152/physrev.00026.2006.
Estrogen Receptors: How Do They Signal
and What Are Their Targets
NINA HELDRING, ASHLEY PIKE, SANDRA ANDERSSON, JASON MATTHEWS, GUOJUN CHENG,
JOHAN HARTMAN, MICHEL TUJAGUE, ANDERS STRÖM, ECKARDT TREUTER, MARGARET WARNER,
AND JAN-ÅKE GUSTAFSSON
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Structural Genomics
Consortium, Botnar Research Centre, University of Oxford, Headington, Oxford, United Kingdom; and
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
I. Introduction
II. Estrogen Receptors
A. Two ER subtypes and several isoforms
B. Diverse structures of synthetic, dietary, and environmental estrogens
C. Distinct molecular pathways involving ERs
III. Estrogen Signaling
A. Estrogen regulation of growth factor pathways and branching morphogenesis in the mammary
gland, prostate, and lung
B. Imprinting by estrogen
C. Estrogen as a trophic factor for neurons
D. ERs and cell adhesion
IV. Anti-Estrogen Signaling
A. Anti-estrogens: benefits and limitations
B. Complete blocking of estrogen signaling
C. Deleterious effects of anti-estrogens
D. Structural basis for ER activity
E. Role of helix 12 in the regulation of AF-2 activity
F. Classical AF-2 antagonism
G. Nonclassical AF-2 antagonism
H. Coregulator recognition of antagonist-bound ER
I. ER coregulators
V. Concluding Remarks
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Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Ström A, Treuter E, Warner
M, Gustafsson J-Å. Estrogen Receptors: How Do They Signal and What Are Their Targets. Physiol Rev 87: 905–931,
2007; doi:10.1152/physrev.00026.2006.—During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a balance
between two opposing forces in the form of two distinct receptors (ER␣ and ER␤) and their splice variants. The
prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes
new and promising therapeutic opportunities in clinical areas as diverse as hormone replacement, autoimmune
diseases, prostate and breast cancer, and depression. Molecular biological, biochemical, and structural studies
have generated information which is invaluable for the development of more selective and effective ER ligands. We
have also become aware that ERs do not function by themselves but require a number of coregulatory proteins
whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important
morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth
factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and
estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on
several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the
molecular mechanisms of anti-estrogen signaling.
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0031-9333/07 $18.00 Copyright © 2007 the American Physiological Society
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I. INTRODUCTION
Estrogens play key roles in development and maintenance of normal sexual and reproductive function. In
addition, in both men and women they exert a vast range
of biological effects in the cardiovascular, musculoskeletal, immune, and central nervous systems (73). The most
potent estrogen produced in the body is 17␤-estradiol
(E2) (Fig. 1). Two metabolites of E2, estrone and estriol,
although they are high-affinity ligands (121) are much
weaker agonists on estrogen receptors (ERs). These metabolites were formally thought to be inactive, but recent
evidence suggests that they may well have tissue-specific
roles (71). The ground-breaking findings in the field were
made in the late 1950s when Elwood Jensen (97) discovered and started the characterization of an estrogen binding protein, today recognized as ER␣. In 1993, nearly
three decades later, the first ER␣ knockout mouse was
created (150), and the surprising discovery was made that
life is possible without this receptor which, at the time,
was thought to be the sole mediator of estrogen signaling.
Soon after the characterization of the ER␣ knockout
mouse, ER␤ was discovered (122), and this discovery
raised the question of whether survival of the ER␣ knockout mouse was due to ER␤ substituting for the functions
of ER␣. ER␤ knockout mice were made, and this was
followed by double ER␣␤ knockouts (120). These different mouse models revealed that life is possible without
either or both ERs but that reproductive functions are
severely impaired (29). In addition, ER␣ and ER␤ were
found to have distinct, nonredundant roles in the immune,
skeletal, cardiovascular, and central nervous systems (29,
73, 78). Some of the most remarkable phenotypes of the
ER␣ and ER␤ knockout mice are the effects on morphogenesis. Estrogen is well known to be a morphogen, and
its role in morphogenesis is evident from the structure of
the uterus (29), ovary (29), mammary gland (54), prostate
(313), lung (181), and brain (301) of ER␣ and ER␤ knockout mice. At the promoters of some genes, particularly
those involved in proliferation, ER␣ and ER␤ can have
opposite actions (145), a finding which suggests that the
overall proliferative response to E2 is the result of a
balance between ER␣ and ER␤ signaling. Anti-estrogens,
designed to block ER␣, are widely and effectively used
clinically in the treatment of breast cancer (28, 43). However, although synthetic anti-estrogens are mainline ther-
FIG. 1. Molecular structures of the endogenous estrogen 17␤-estradiol and of tamoxifen, 4-hydroxy-tamoxifen,
raloxifene, ICI 182,780 (fulvestrant), toremifene, R,R-cisdiethyl-THC, and genistein.
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apy for treating ER␣-positive breast cancers, these drugs
have unwanted side effects in nontarget tissues, and after
prolonged treatment, cancers become resistant to antiestrogen therapy (197, 256). The idea that ER␤ agonists
may be used to promote growth arrest offers new possibilities for pharmacological intervention in the treatment
of cancers (179, 221). The mechanisms governing the
action and development of resistance to anti-estrogens
are poorly understood. The emerging picture is one in
which ER is capable of adopting a multitude of response
states depending on the nature of the bound ligand
(Table 3 and references therein) and where each ligand
induces a unique receptor conformation capable of recruiting a distinct pattern of coactivators and corepressors to the receptor-transcription complex.
In this review we focus on new insights into estrogen
receptor modulation by synthetic anti-estrogens and coregulatory proteins and discuss the molecular concept of
anti-estrogen signaling. We also discuss the roles of ER␣
and ER␤ in mediating growth and morphogenesis.
II. ESTROGEN RECEPTORS
A. Two ER Subtypes and Several Isoforms
Cellular signaling of estrogens is mediated through
two ERs, ER␣ (NR3A1) and ER␤ (NR3A2), both belonging
to the nuclear receptor (NR) family of transcription factors. Like many other members of the NR family, ERs
contain evolutionarily conserved structurally and functionally distinct domains (Fig. 2). The central and most
conserved domain, the DNA-binding domain (DBD), is
involved in DNA recognition and binding, whereas ligand
binding occurs in the COOH-terminal multifunctional ligand-binding domain (LBD). The NH2-terminal domain is
not conserved and represents the most variable domain
both in sequence and length. Transcriptional activation is
facilitated by two distinct activation functions (AF), the
constitutively active AF-1 located at the NH2 terminus of
the receptor and the ligand-dependent AF-2 that resides in
the COOH-terminal LBD (reviewed in Ref. 194). Both AF
domains recruit a range of coregulatory protein complexes to the DNA-bound receptor. The two ERs share a
high degree of sequence homology except in their NH2terminal domains, and they have similar affinities for E2
and bind the same DNA response elements.
Ligand-dependent estrogen signaling begins with the
binding of estrogen to ER. Thereafter, the cell-specific
transcriptional response to estrogen depends on multiple
factors, the most immediate being the composition of
coregulatory proteins in a given cell and the characteristics of the promoters of estrogen responsive genes. Since
hormones are modulators of transcription, the pattern of
modulated genes also depends on what other signaling
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FIG. 2. Schematic representation of described estrogen receptor
(ER) isoforms. The domains of the receptors include DBD, LBD, and two
transcriptional activation functions, AF-1 and AF-2 as indicated for
hER␣. Full-length human ER␣ is 595 amino acids long (69). Both short
ER␣ isoforms, hER␣-46 and hER␣-36, lack the NH2-terminal region
harboring AF-1 (52, 305). Percent sequence similarity between hER␣
wild-type and hER␤ is indicated in hER␤. The 530-amino acid-long hER␤
isoform is currently regarded as the full-length wild-type hER␤ (140).
Note that deletion of the fifth exon giving the hER␤⌬ exon 5 isoform
results in a frameshift and a termination of the protein before the LBD
(93). The striped fill patterns of the 3⬘ end of hER␤2 (also named
hER␤cx), hER␤4, and hER␤5 represent the differing COOH-terminal
regions of these isoforms (180, 204, 234). The full-length rat and mouse
ER␤ isoforms are 549 amino acids (46, 296) and have 99% sequence
similarity. The mER␤2 and rER␤2 isoforms contain an 18-amino acid
insertion in the LBD (25, 149), causing a significant decrease in ligand
binding affinity (148). Deletion of exon 3 results in rat isoforms unable
to bind DNA (227, 235), and the observed deletion of exon 5 and/or 6 in
mice results in isoforms lacking various parts of the LBD (149).
pathways are active in the cell at the time of hormone
exposure (108, 110, 194).
The identification of the second estrogen receptor
ER␤ and several receptor isoforms has affirmed the complex nature of estrogen signaling and helped to explain
estrogen action in tissues that do not express ER␣. ER␣
and ER␤ are products of separate genes located on different chromosomes (46, 172). Several splice variants
have been described for both receptor subtypes (Fig. 2),
but whether all the variants are expressed as functional
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proteins with biological functions is not clear. Most ER␣
variants differ in their 5⬘-untranslated region (UTR), not
in the coding sequence. In addition, shorter ER␣ isoforms
lacking exon 1 and consequently the NH2-terminal AF-1
(here termed hER␣-46 and hER␣-36) have been isolated
and identified in different cell lines (52, 305). These receptor isoforms have not yet been identified or characterized in tissues, and their involvement in regulating estrogen effects in vivo remains to be determined. They are,
however, interesting research tools since they have the
ability to heterodimerize with the full-length ER␣ and
thereby repress AF-1-mediated activity (52, 305). Possibly,
they may also localize to the plasma membrane and may
help to elucidate the mechanisms through which rapid,
“nongenomic” estrogen signaling occurs (144, 305). Unlike ER␣, several splice variants of ER␤ are expressed in
tissues. The 530-amino acid (aa)-long human ER␤ isoform
is currently regarded as the wild-type ER␤ (rat and
mouse, 549 aa) (140). Several alternative ER␤ isoforms
have been described (Fig. 2), and many of these are
expressed as proteins in tissues (59, 252). Characterization of the functional isoform pattern in human samples is
not complete, but several experiments indicate that ER␤
isoforms can differentially modulate estrogen signaling
and, as a consequence, impact target gene regulation (137,
167, 242). For example, the human ER␤2 isoform (also
named ER␤ cx) with 26 unique aa residues replacing the
COOH-terminal part of the LBD is unable to bind ligand or
coactivators and has no transcriptional activity in reporter assays. ER␤2 dimerizes with preferentially ER␣,
thereby silencing signaling via this ER isoform (204). Both
species-specific and species-common ER␤ isoforms have
been identified (reviewed in Ref. 139) (Fig. 2).
disruptors. Altered reproductive capacity in wildlife and
cancers in the breast and endometrium are thought to be
possible consequences of exposure to endocrine disruptors (133, 319). On the other hand, epidemiological studies suggest that diets rich in phytoestrogens, particularly
soy and unrefined grain products, may be associated with
decreased risk of some hormone-induced cancers (reviewed in Ref. 318). Numerous investigations have documented antiproliferative effects of genistein, the most
abundant phytoestrogen in soy. Genistein (Fig. 1) has a
ninefold higher affinity for ER␤ than for ER␣ (5, 121).
Because of its ER␤ selectivity, genistein would be expected to have none of the unwanted side effects of
estrogen replacement on the endometrium. Whether or
not genistein by itself is adequate in replacing the effects
of estrogen on bone, brain, and cardiovascular and immune systems is at present under intense investigation
(reviewed in Refs. 212, 315, 324).
A variety of synthetic estrogen antagonists have been
developed, and some of them are used clinically to reverse the growth-promoting effects of estrogens in breast
cancers (Fig. 1) (reviewed in Refs. 247, 262). Additional
compounds have been developed and characterized to
obtain more favorable tissue and receptor subtype selective effects (reviewed in Refs. 109, 299). The term SERM
(selective estrogen receptor modulator) describes synthetic ER ligands that display tissue-selective pharmacology. As anti-estrogens (or antagonists) they oppose the
action of estrogens in certain tissues, while mimicking the
action of endogenous estrogens (agonists) in others (108,
110). The mechanism of anti-estrogen signaling is discussed in detail below. Hereafter in the review, the term
anti-estrogen will be used rather than SERM, since the
latter term encompasses a wider concept.
B. Diverse Structures of Synthetic, Dietary, and
Environmental Estrogens
C. Distinct Molecular Pathways Involving ERs
In contrast to the situation for some NRs, such as the
thyroid hormone receptor (TR) or the retinoic acid receptor (RAR), where the shape of the ligand-binding cavity is
well adapted to fit the cognate hormone, ERs⬘ ligand
cavity appears generous in size for E2 (22). This allows
ER to bind a wide range of compounds with strikingly
diverse structures. In addition to estrogens, ERs also
show affinity for environmental contaminants such as
polycyclic aromatic hydrocarbons, phthalates, and pesticides, a class of estrogens termed xenoestrogens (20).
Certain plant constituents termed phytoestrogens (101,
209) also have estrogenic actions that are biologically
relevant in humans as well as in farm animals.
Environmental contaminants with estrogenic activity
are thought to interfere with endocrine signaling in estrogen-responsive tissues and are referred to as endocrine
Emerging evidence suggests that there are several
distinct pathways by which estrogens and ERs may regulate biological processes (74) (Fig. 3). Ligand-bound ERs
can bind directly to estrogen response elements (ERE), in
the promoters of target genes or can interact with other
transcription factor complexes like Fos/Jun (AP-1responsive elements) (127) or SP-1 (GC-rich SP-1 motifs)
(255) and influence transcription of genes whose promoters do not harbor EREs. Ligand-dependent activation triggers recruitment of a variety of coregulators to the receptor in a complex that alters chromatin structure and facilitates recruitment of the RNA polymerase II (Pol II)
transcriptional machinery. The details of ER-transcription
factor interactions (i.e., ligand specificity, ER subtype
specificity, interaction domains and motifs) remains to be
characterized. Interestingly, in certain cell-type and pro-
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FIG. 3. Model representing the mechanistically distinct molecular pathways used in the regulatory actions of ERs. The classical (direct) pathway
includes ligand activation and a direct DNA binding to estrogen response elements (ERE) before modulation of gene regulation. The tethered
pathway includes protein-protein interaction with other transcription factors after ligand activation, and thereby gene regulation is affected by
indirect DNA binding. A third mechanism, also called nongenomic with rapid effects, is not as well understood as the genomic mechanism but has
been observed in many tissues. The ligand activates a receptor, possibly associated with the membrane; either it is a classical ER (33, 138, 243), an
ER isoform (141, 305), or a distinct receptor (38) or, alternatively, a signal activates a classical ER located in the cytoplasm. After this rather unclear
event, signaling cascades are initiated via second messengers (SM) that affect ion channels or increase nitric oxide levels in the cytoplasm, and this
ultimately leads to a rapid physiological response without involving gene regulation. The ligand-independent pathway includes activation through
other signaling pathways, like growth factor signaling. In this case, activated kinases phosphorylate ERs and thereby activate them to dimerize, bind
DNA, and regulate genes.
moter contexts, 4-hydroxytamoxifen and raloxifene,
which function as antagonists at EREs, can behave as
agonists through these indirect pathways. ER␤, but not
ER␣, in the presence of E2 can oppose the actions of
4-hydroxytamoxifen and raloxifene on an AP-1 reporter
gene (127, 216, 309, 312). Similar observations have been
made for the SP-1 pathway (255, 331).
In addition to the well-studied transcriptional effects
of E2, there are rapid effects, i.e., occurring within seconds or minutes after addition of E2 (283, 284, 307; reviewed in Refs. 274, 320). These rapid effects include
activation of kinases and phosphatases and increases in
ion fluxes across membranes. Although these rapid effects have been extensively studied, there is still no consensus as to whether or not the classical ERs are involved
(33, 138, 243) or whether there is a distinct membraneassociated receptor (38). Tools such as pathway-selective
ligands (77) or cell lines designed to selectively express
ER␣ in the nucleus, cytoplasm, or membrane may prove
useful in studying these extranuclear ER actions (253).
Interestingly, evolutionary evidence suggests that early
on, estrogen influenced reproduction through ER-independent pathways (111) and that the receptor was unrePhysiol Rev • VOL
sponsive to estrogens and acted as a constitutive transcriptional activator (111, 291).
When the two ER subtypes are coexpressed in cells,
ER␤ can antagonize ER␣-dependent transcription (167,
168). The molecular mechanisms of ER␤-mediated inhibition of ER␣ signaling are currently under investigation.
For example, it was shown that for ER␣-mediated regulation of AP-1-dependent transcription, ER␤ expression
alters the recruitment patterns of c-Fos to AP-1-regulated
promoters (168). Moreover, expression of ER␤ and the
ER␤ variant ER␤2 increases the proteolytic degradation
of ER␣ (168). Collectively, these data suggest that the
ER␤-mediated inhibition of ER␣ activity involves a combination of altered recruitment of key transcription factors and increased ER␣ degradation.
In addition to ligand-induced transcriptional activities of ER, ligand-independent pathways to activate ERs
have been described. Growth factor signaling leads to
activation of kinases that may phosphorylate and thereby
activate ERs or associated coregulators in the absence of
ligand (106). The growth factor activated pathway is
thought to significantly contribute to hormone-independent growth in some tumors (30, 269).
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III. ESTROGEN SIGNALING
A. Estrogen Regulation of Growth Factor
Pathways and Branching Morphogenesis in the
Mammary Gland, Prostate, and Lung
Estrogens and androgens are necessary for initiating
programs of morphogenesis at specific times during development, but it is growth factors and their receptors
that are needed for communication between epithelium
and mesenchyme. Without this communication, morphogenesis cannot occur. The major players in the cross-talk
between epithelium and mesenchyme are the epidermal
growth factor pathway, which includes epidermal growth
factor receptor (stromal), epidermal growth factors (epithelial), and the proteases which activate them (epithelial
and stromal); FGF receptors (epithelial) and their ligands
(stromal); the transforming growth factor beta family of
peptides (BMPs) (stromal) and their receptors; and the
Notch signaling pathway (epithelial receptors).
Epidermal growth factor receptor (EGFR-1; also
called HER-1 and ErbB-1) is essential for epithelial development, tissue repair, tumor growth, tissue-modeling phenomena, angiogenesis, and fibrogenesis. EGFR is activated by six peptide growth factors: EGF, transforming
growth factor (TGF)-␣, betacellulin, heparin-binding EGF
(HB-EGF), amphiregulin, and epiregulin. These are all
expressed as transmembrane precursors that need to be
released from the cell surface by proteolysis (79). The
proteases which activate EGF receptor ligands are members of a disintegrin and metalloproteinase family
(ADAM) of cell surface proteases. Thus tissue selectivity
in regulation of EGF signaling depends on the type of EGF
receptor, the type of protease, and the type of ligand
expressed in the tissue.
1. Mammary gland morphogenesis
Ductal elongation in the mammary gland is absolutely dependent on ER␣ and does not occur in ER␣⫺/⫺
mice. When pituitary hormones are normalized and prolactin, progesterone, and estrogen are administered to
ER␣⫺/⫺ mice, a truncated mammary structure results.
There is abundant alveolar growth but no ductal elongation. Kenney et al. (113) transplanted ER␣⫺/⫺ virgin
mammary glands into the cleared mammary fat pad of
virgin wild-type (wt) or ER␣⫺/⫺ mice and found that wt
mammary tissue failed to grow in ER␣⫺/⫺ mammary fat
pads. On the other hand, in ER␣⫺/⫺ mammary glands,
there was lobulo-alveolar growth in wt mouse fat pads.
Treatment of virgin ER␣⫺/⫺ mammary gland with TGF-␣
or heregulin ␤1 stimulated growth and secretory activity
(113). It is not only in tissue recombinants that wt epithelium fails to penetrate ER␣⫺/⫺ fat pad. When 3-wk-old
ER␣⫺/⫺ fat pad is implanted into the mammary fat pad of
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a 3-wk-old wt mouse, ducts avoid the ER␣⫺/⫺ implant.
This strongly indicates that the ER␣⫺/⫺ fat pad secretes
growth inhibitory substances. At 3 wk of age, the stroma
of the mammary gland expresses both ER␣ and ER␤
(Fig. 4). We speculate that ER␤ stimulates secretion of a
growth repressor. One possible factor is TGF-␤, which is
an estrogen-regulated gene (94).
The use of knockout mice (119, 133, 152, 161, 225,
250, 266) and tissue recombination methods (286) have
revealed that ADAM-17 is responsible for processing of
TGF and HB-EGF and that mammary ductal growth is
dependent on epithelial amphiregulin and stromal EGFR.
ADAM-17 is essential for branching, but other metalloproteinases (MMP) are involved in remodeling of the mammary gland (272, 317). Degradation of ECM proteins by
MMPs clears a path for migration of epithelial cells during
ductal growth. In addition, cleavage of some proteins
(elastin, laminin-5, or collagen types IV or VII) releases
growth factors that facilitate growth and migration of
epithelial cells (104, 119). Inhibitors of metalloproteinase
activity, TIMPs, modulate MMP functions. EGF and MMP
signaling are not independent processes but are essential
parts of a well-regulated system. Exposure of breast epithelial cells in culture to the EGFR ligand amphiregulin
induces expression of MMP2 and MMP9 (173).
Tissue recombinant experiments with fetal tissues
have shown that stromal, not epithelial, ER␣ is needed
during mammary gland morphogenesis (32) and that
EGFR phosphorylation and ductal development only occur when ADAM-17 and amphiregulin are expressed on
mammary epithelial cells, whereas EGFR is required in
the stroma (286). These tissue recombinant experiments
indicate that ER␣ is not required for expression of EGFR
ligands or for expression of ADAM-17 in epithelial cells
during morphogenesis. One working scenario for the role
of ER␣ in mammary gland morphogenesis is that stromal
ER␣ induces ADAM-17, which stimulates release of amphiregulin from epithelial cells in the terminal end buds.
Amphiregulin activates EGFR in nearby stromal cells. In
this way epithelium and stroma communicate with each
other in coordinating ductal growth. This mechanism is
valid during the limited time when ER␣ is expressed in
the stroma. Our own data show that this is during weeks
2– 4 of postnatal life (Fig. 5). ADAM-17⫺/⫺ (55, 286),
amphiregulin⫺/⫺ (151, 286), and ER␣ ⫺/⫺ mice (113) all
show impaired ductal elongation. EGF receptor⫺/⫺ mice
do not survive the perinatal period (175).
Mammary lobular/alveolar growth does not require
ER␣ or EGF (314). The requirement for estrogen in alveolar growth in ER␣⫺/⫺ mice suggests that ER␤ may be
involved in alveologenesis and epithelial cell differentiation. Such a role for ER␤ is consistent with the finding of
incomplete differentiation of the mammary epithelium
in ER␤⫺/⫺ mice (54). There is a normal ductal tree in
ER␤⫺/⫺ mice, but as these mice age, the epithelium in
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FIG. 4. In the adult mouse mammary gland, ⬎60% of the ductal epithelial cells express ER␤ and ⬍20% express ER␣. ER␣ is not found in the
stroma of the adult gland but ER␤ is. In the 2-wk-old mouse, both ER␣ and ER␤ are strongly expressed in both the epithelium and stroma.
the mammary gland continues to express the proliferation
marker Ki67 and to proliferate. The gland becomes filled
with large cysts. Mammary epithelial proliferation in
ER␤⫺/⫺ mice between 1.5 and 2 yr of age appears to be
independent of estrogen, since at this age the ovaries are
depleted of follicles (Fig. 5). Our working hypothesis is
that loss of ER␤ leads to loss of TGF-␤ and loss of a major
growth repressor in the mammary gland.
2. Prostate morphogenesis
Some of the most compelling evidence for a role of
estrogen during embryogenesis is the outcome of in utero
exposure to the synthetic estrogen diethylstilbestrol
(DES). Both males and females, who were exposed in
utero, develop in adulthood a wide range of abnormalities
in their urogenital tracts. In the 1980s, the McLachlan
laboratory pioneered the use of DES in mice for investigating the mechanism of the human DES syndrome. PerPhysiol Rev • VOL
manent alterations occur in the male and female genital
tracts when mice are exposed to DES at certain critical
times during development. In male mice, prenatal exposure to DES is associated with poor semen quality, prostatic disease, cryptorchidism, testicular neoplasia, feminization of the seminal vesicles (induction of the estrogen
responsiveness and of the estrogen-regulated gene lactotransferrin), and stromal inflammation (9, 190, 240). Imprinting by DES in the developing prostate is absolutely
dependent on the presence of ER␣, and ER␣⫺/⫺ mice are
resistant to imprinting by DES (238).
It is, therefore, not surprising that the structure of the
prostates of ER␣⫺/⫺ mice are abnormal (206). Surprisingly, unlike the case in the mammary gland, the ER␣⫺/⫺
mouse ventral prostate is characterized by extremely long
distended ducts with little branching and very sparse
periductal stroma. This phenotype is compatible with the
suggestion that ER␣ is a positive regulator of secondary
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FIG. 5. In wild-type mice at 2 yr of age, there are still follicles and corpora lutea in the ovaries. In the ER␤⫺/⫺ mouse ovary, there are no follicles
and no evidence of corpora lutea. The ducts of mammary glands of 2-yr-old wild-type mice are atrophic (small arrows) with no evidence of the
proliferation marker Ki67. In ER␤⫺/⫺ mice, ducts are large and cystic (long arrows) and many cells express Ki67.
branching and of stromal growth. How might ER␣ be a
positive regulator of secondary branching? The ER␣⫺/⫺
prostate is not unlike that of the prostate of mice treated
with EGF, i.e., increased prostatic size, with reduced
ductal branching and swollen ducts.
Tissue recombinant experiments have shown that
like the mammary gland, prostatic growth requires ER␣
signaling in the mesenchyme, not in the epithelium, and
this is compatible with the idea that a mesenchymal
growth factor is ER␣ regulated. Testosterone produced
by the fetal testes drives prostate morphogenesis, but
ductal elongation and branching involve a close communication between the urogenital mesenchyme and epithelium, and this communication involves positive regulation
by ER␣, FGF10, Shh, and repressive activity of BMPs (15,
37). Although FGF10 is a prostatic mesenchymal growth
factor, available data show that it is not regulated by
androgens (290).
BMP7 secreted from the stroma is a repressor of
Notch signaling and thus of branching morphogenesis
(132). Follistatin, an estrogen-regulated gene produced in
the epithelium, is an inhibitor of BMP signaling (105). The
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transient expression of ER␣ observed in prostate epithelium in the first 2 wk of life (206) leaves open the possibility that ER␣ may, at this time, regulate follistatin expression. ER␣ would then induce a repressor of a repressor and would thus be a positive regulator of notch
signaling and branching. In ER␣⫺/⫺ mice, secretion of
follistatin from the epithelium would be repressed and the
BMP would be free to inhibit branching. BMP7 is expressed in the periurethral urogenital mesenchyme prior
to formation of the prostate buds. In BMP7 null mice,
Notch1 signaling is derepressed in the urogenital epithelium (70, 302, 303). Both ER␣ and EB␤ oppose BMP
signaling (327).
The original description of the ventral prostate of
adult, neonatally estrogenized rats [elevated expression
of the androgen receptor, a continuous layer of basal
cells, an increase in interacinar stromal tissue, disorganized acini with epithelial hyperplasia, luminal sloughing,
lack of epithelial differentiation, and a remarkable reduction in expression of ER␤ (236, 237, 239, 321)] are
characteristics of the phenotype of the ER␤⫺/⫺ mouse
ventral prostate (92, 313), and we speculate that these
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ESTROGEN RECEPTOR SIGNALING
characteristics of the adult prostates of neonatally estrogenized mice are a consequence of the reduction in
ER␤ expression in the prostates of these mice (236, 237,
239, 321).
Recently, the Prins laboratory demonstrated that one
of the genes that is downregulated by neonatal estrogen
exposure is FGF10. This then leads to downregulation of
sonic hedgehog-patched Gli (Shh-ptc-gli) and BMP7. Thus
ER␣ directly or indirectly is a repressor of BMP7, and the
branching defects in the dorsolateral prostate of neonatally estrogenized mice can be explained by the loss of
Shh-ptc-gli and BMP7 signaling (90).
Interestingly, according to Prins, FGF10, Shh-ptc-gli
and BMP7 are not reduced in the ventral lobes of the
prostate following neonatal estrogenization. This difference in lobe-specific expression of these factors explains
why there are more serious branching deficits in the
dorsal than the ventral lobe. It leaves unanswered the
questions of why the structure and size of the ventral lobe
are so profoundly affected by neonatal estrogenization
and why FGF10 in the ventral prostate lobe is insensitive
to neonatal estrogen. FGF signaling is androgen dependent: the urogenital sinus of FGF10⫺/⫺ mice in culture
can be stimulated to produce prostate buds by FGF10
plus testosterone but not by FGF10 alone. The requirement for both testosterone and FGF10 for the growth of
prostatic buds suggests that testosterone, not estrogen, is
essential for expression of FGF receptors in the epithelium. The observed high expression of androgen receptors in the ventral prostate of neonatally estrogenized
mice might help explain the maintenance of FGF10 signaling in this tissue.
If loss of ER␤ results in profound morphological
changes in the ventral prostate, what are the ER␤ regulated genes that lead to these abnormalities? To answer
this question we have to examine the epithelium of the
adult ventral prostate for growth factors that are estrogen
repressed or growth repressors whose expression is increased by estrogen. TGF-␤ is an estrogen-stimulated
growth repressor (94) that inhibits both testosterone- and
EGF-stimulated prostatic stromal and epithelial cell
growth. Epithelial and stromal cells from 20-day-old rat
ventral prostate express the mRNA for TGF-␤1, -2, and -3.
TGF-␤2 mRNA expression is elevated at birth, declines
during the period of prostate growth, and is elevated
again at 100 days of age (94). Its expression is also increased in the prostate upon castration of adult rats. This
pattern of expression is compatible with a role for TGF-␤
in limiting prostate growth (1). Since ER␤ is the only ER
expressed in the adult ventral prostate epithelium, estrogen regulation of TGF-␤ is most likely mediated by ER␤.
This would mean that ER␤ has a role in limiting alveolar
growth in the prostate.
Physiol Rev • VOL
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3. Lung morphogenesis
The lungs of adult ER␤⫺/⫺ mice are characterized
by decreased elastic tissue recoil (164, 165) and an increased expression of MMP1 and TIMP2, and cleaved
(active) MMP2 (181). Alterations in the proteolytic/antiproteolytic balance of the lung have been associated with
several respiratory diseases characterized by changes in
the lung extracellular matrix (ECM). So it is not surprising
that in the lungs of ER␤⫺/⫺ mice there is accumulation of
collagen and that suboptimal lung function leads to overall hypoxia in these mice (181). ER␤ is abundantly expressed in epithelial cells in the adult lung, and the elevated levels of expression of MMP1 and TIMP2 in
ER␤⫺/⫺ mice indicates that ER␤ might normally suppress this complex and restrict activation of MMP2.
Both EGF and FGF signaling are essential for development of lungs. EGFR is essential for epithelial-mesenchymal interactions, and the lungs of EGFR⫺/⫺ mice are
so impaired that mice do not survive the perinatal period
(175). Embryonic lung synthesizes several EGFR ligands
and responds to EGF, TGF-␣, and amphiregulin by precocious branching (259, 306). FGF10 is expressed in lung
mesenchyme during branching morphogenesis (E10.5–
16.5) and is an essential nonredundant growth factor
(107). Transgenic mice expressing a dominant negative
FGF receptor specifically in lung tissue do not develop
lungs (226). The severe phenotypes of both the
FGF10⫺/⫺ and the EGFR⫺/⫺ mice are not seen in the
ER␤⫺/⫺ mouse. Lungs of ER␤⫺/⫺ mice are morphologically indistinguishable from those of their wt littermates
until mice are 5 mo of age. Expression of ER␣ and ER␤ in
the embryonic lung has not been reported, and we do not
know whether ER␤ plays a role in lung development or
whether it only functions in remodeling of the adult lung.
Ryu et al. (249) have shown that fetal human lung is
characterized by high levels of MMP-2 and little TIMP-3
expression while the adult human lung exhibits a more
antiproteolytic profile with decreased MMP-2 and increased TIMP-3 expression. The MMP profile in the
ER␤⫺/⫺ mouse lung resembles that of the fetal rather
than the adult human lung and may reflect a block in
maturation as is seen in epithelium of other organs in
ER␤⫺/⫺ mice.
B. Imprinting by Estrogen
Several distinct critical periods or “windows in time”
when estrogen influences tissue morphogenesis have
been observed for many organs. In 1975, the Naftolin
laboratory made the astounding observation that in rodents, estrogen masculinizes hypothalamic neurons on
embryonic day 18 (185). The estrogen for this masculinization is synthesized in the embryonic brain from testosterone produced in the testes, and this transient exposure
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HELDRING ET AL.
to estrogen initiates a critical period of sexual differentiation of the brain (reviewed in Ref. 184). We now know
that there are even earlier time points in development
when estrogen can influence brain function. In 1992 Beyer
et al. (17) showed that sexual differentiation in prolactin
expression of certain diencephalic neurons occurs before
the testosterone surge, and in 2001 studies on the brains
of ER␤⫺/⫺ mice revealed that ER␤ influences neuronal
survival as early as embryonic day 15 (301). For the
uterus, vagina, prostate, and lung, one critical period
when estrogen influences morphogenesis is between embryonic days 9 and 16. There is a second critical period
between postnatal days 1 and 6 when the prostate and the
skeleton are imprinted (176). In the developing mammary
gland on the other hand, estrogen influences morphogenesis at puberty.
C. Estrogen as a Trophic Factor for Neurons
Some 30 years ago, it was found that estrogen enhances the growth and arborization of axons and dendrites in hypothalamic neurons grown in organotypic cultures (294). Neonatal estrogen treatment of rats has been
shown to increase synapse formation in the arcuate nucleus during postnatal development (3) and to restore
deafferentation-induced loss of axodendritic synapses in
adults (166). Synapse remodeling in adults does not occur
only in response to axonal injury but is a continuously
ongoing process involved in memory and learning. Synapses in the arcuate nucleus and in the CA1 region of the
hippocampus exhibit a phasic remodeling, coordinated
with fluctuation in hormone levels during the estrous
cycle (205). Growth-promoting effects of estrogen have
also been described in the midbrain (244), cortex (62),
hippocampus (68), spinal cord (298), and pituitary (26).
It is generally accepted that in the early postnatal
period as well as in adults, changes in the morphology of
synapses and increased number of dendritic spines can
account for many of the estrogen-induced changes in
brain morphology, sexual behavior, and memory and
learning.
Effects of estrogens on neuronal growth are mediated via regulation of endogenous neurotrophic substances. Estrogen regulates nerve growth factor (NGF)
and its receptors in cholinergic neurons (293), TGF-␤ in
the hypothalamus (155), brain-derived neurotrophic factor in the cortex (281), NGF receptors in sensory neurons
(280), and the insulin-like growth factor and its receptor
in the hypothalamus (42, 233).
As in peripheral tissues, the effects of estrogen on
growth factor signaling are reciprocated, and growth factors can influence estrogen signaling. Thus NGF has been
shown to regulate ER action in the forebrain, possibly via
phosphorylation events (177). However, estrogen can also
Physiol Rev • VOL
affect neurite elongation and differentiation directly
through its regulation of cytoskeletal genes that are required for neurite growth (49, 154, 260).
Both ER␣ and ER␤ are expressed in the adult rat
brain with ER␤ mRNA-containing cells more widely dispersed throughout the brain than those expressing ER␣
mRNA (12, 36, 129, 213, 270). Comparison of ER mRNA
expression patterns in rat, mouse (125, 270), monkey (72),
and human (214, 215) indicates that, although the general
distribution is similar, data cannot be extrapolated from
one species to another. The paraventricular nucleus of
rats has been reported to express only ER␤, while in the
mouse it contains cells that also express ER␣. The human
paraventricular nucleus has been reported to express
mRNA for both ER␣ and ER␤, with ER␣ predominating.
In addition to the well-characterized role of estrogen
on feedback regulation of hypothalamic and pituitary hormone secretion (102) and facilitation of female reproductive behavior (157), estrogen also has effects on the modulation of motor behavior (8) and on mood and mental
state (50, 76). More recently, estrogen has been recognized as a neuroprotective agent. The use of estrogen to
protect against Alzheimer’s disease, Parkinson’s disease,
schizophrenia, and ischemic stroke (16, 153, 258, 275, 276)
is being widely debated at present. Multiple epidemiological reports have suggested that estrogen replacement
may delay the onset of and slow the cognitive decline
associated with Alzheimer’s disease (reviewed in Ref.
264). In some studies estrogen showed no beneficial effects on cognition (182, 271). Suggestions for possible
mechanisms through which estrogen might exert positive
effects in the brain include prevention of amyloid
␤-plaques (10, 67, 325) and regulation of apoptosis. Several studies have shown that estrogen can modulate expression of the antiapoptotic proteins Bcl-2 and/or Bcl-xL
(the long isoform of Bcl-x) in hippocampal, cortical, and
dorsal root ganglion neurons (41, 193, 222). In addition,
estrogen can downregulate expression of the proapoptotic Bad or Nip-2, which is a negative regulator of Bcl-2
(21, 66).
Perhaps the optimal strategy for estrogen replacement still has to be worked out. It seems that there is a
critical period around the menopause, and if estrogen
replacement therapy is used early after menopause it
delays the onset of and slows the cognitive decline. However, estrogen replacement therapy at a later stage does
not seem to improve the cognitive function. It also still
remains to be determined whether selective ER␣ and ER␤
agonists might be more effective than the conjugated
estrogens currently used.
D. ERs and Cell Adhesion
Adhesion between neighboring cells and cell adhesion to the ECM influence the structure of normal epithe-
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ESTROGEN RECEPTOR SIGNALING
lium as well as cell migration and invasion during tumorigenesis and metastasis. Estrogen signaling plays a significant role in the regulation of these processes, particularly
in the mammary gland. In the MCF7 breast cancer cell
line, estrogen stimulates morphological changes associated with the rearrangement of intermediate and actin
filaments and modifications in the formation of cell-cell
and cell-ECM adhesion plaques (35, 254). During tumorigenesis there are alterations in expression of adhesion
molecules and proteins involved in cell migration (reviewed in Ref. 31). Expression of the cadherin and catenin
families, CD44, integrins and metalloproteases are all
changed in cancer. E-cadherin is highly expressed in ER␣positive, low-grade tumors (220, 282), while P-cadherin is
present in ER␣-negative, high-grade tumors (128, 218).
From studies on the ER␤⫺/⫺ mouse mammary gland
(54), it appears that ER␤ positively regulates the terminal
differentiation of the mammary gland epithelium. The loss
of ER␤ results in a reduction of the ECM and lamina
basalis and, frequently, in an increase of the interepithelial cell space, characterized by decreased levels of the
adhesion molecules, E-cadherin, connexin 32, occludin,
and integrin ␣2.
During tumor progression, epithelial-to-mesenchymal transition is associated with the loss of adherens
junctions, profound morphological changes, and enhanced migratory and invasive capabilities (reviewed in
Refs. 31, 103). Loss of E-cadherin is a key event in this
progression. The E-box binding transcriptional repressors
Snail, Slug, SIP1, and Twist are key repressors of Ecadherin transcription. Snail in turn is repressed by an E2
regulated gene, the metastatic tumor antigen 3 (MTA3), a
component of the Mi-2/NuRD nucleosome-remodeling
and histone deacetylation complex (58). In mammary epithelial cells, ER␣ is necessary for maintenance of mammary epithelial architecture by constraining Snail repression of E-cadherin. ER␣ with its corepressors NCoR and
SAFB1 can bind to and repress transcription of the Ecadherin promoter (201). Thus E-cadherin expression is
regulated by the cellular ER content, coactivators/corepressors, and active signaling from other pathways.
IV. ANTI-ESTROGEN SIGNALING
Many of the growth-stimulatory effects of estrogens
in breast cancer have been linked to ER␣ (14, 248). Today,
ER␣ expression is routinely checked in pathological diagnosis, and if ER␣ is expressed in the tumor, the patient
receives the anti-estrogen tamoxifen. Seventy percent of
women with ER␣-positive breast cancer benefit from tamoxifen (43a, 100). The usefulness and importance of
tamoxifen in breast cancer therapy is well established,
and the disease-free survival rate has increased drastically due to the widespread use of tamoxifen (24).
Physiol Rev • VOL
915
The potential of ER␤ as a predictive factor in breast
cancer has been under intense scrutiny. Several publications have evaluated ER␤ mRNA in breast cancer, but the
usefulness of ER␤ as a diagnostic marker is still not clear
(39, 219, 251, 285). While ER␤ is the predominant receptor
in the normal breast, its levels are reduced in breast
tumors, and some laboratories have reported on a correlation between the presence of ER␤ and lower tumor
stage and grade (96, 183, 207, 208). Others have found no
correlation of ER␤ protein with clinical parameters (60).
The unwanted agonistic effects of anti-estrogens in
the breast and uterus have traditionally been linked to a
strong AF-1 activity of ER␣, since an effective and specific
structural inhibition of AF-2 activity is seen with these
ligands (Fig. 6). Although the tissue-selective agonist activity of anti-estrogens may be a function of the cell
type-specific set of coregulators, surprisingly few of the
well-known NR and ER coactivators (reviewed in Refs. 6,
163, 279) have been reported to be directly involved in
anti-estrogen signaling (Tables 1, and 2). The contribution
of ER␤ to the tissue-selective agonistic effects of tamoxifen is considered minimal, since the activity of the AF-1
domain in this receptor subtype is almost negligible in
reporter-mediated gene expression (75).
Anti-estrogens were traditionally thought to occupy
the ligand-binding pocket blocking access to E2 and freezing ER in “inactive” conformations that are unfavorable to
coactivator interactions. Current evidence suggests that
cell type-specific profiles of coregulators determine transcriptional activities of antagonist-bound ERs (108, 110,
263). Furthermore, different antagonists induce ligandspecific conformational changes in ERs, allowing exposure of unique surfaces for coregulator interactions (82,
199, 217). These findings, together with recent gene expression profiling data (56, 57, 84), extend the traditional
view of ER antagonist function to include “active antiestrogen signaling.”
A. Anti-estrogens: Benefits and Limitations
When clinically employed as antiproliferative agents
in the treatment of breast cancer, the agonist action of
antiestrogens is desirable in certain tissues like bone and
cardiovascular system, while highly inappropriate in tissues like uterus or breast. Optimization of therapeutic
strategies for targeting hormone-dependent tumors is focused on agents with slightly modified pharmacological
profiles. Raloxifene and toremifene are therapeutically
established anti-estrogens, available for prevention of osteoporosis (18) and treatment of advanced hormone-sensitive breast cancer (80). Since the mechanism of action
of tamoxifen, raloxifene and toremifene are closely related, similarities in their therapeutic profiles are expected. Although raloxifene and toremifene do exhibit the
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FIG. 6. Major conformations induced by ER agonists and antagonists. Schematic representation of ERs bound to E2 (A), E2/LxxLL NR-box (B),
raloxifen (C), genistein (D), and ICI (E). The location of AF-2 between H3-H5 and H12 is indicated in A. The position of H12 is indicated by a green
cylinder. The LxxLL peptide is shown as a purple cylinder with leucines in stick form in B.
same beneficial effects as tamoxifen on bone and on
serum lipoprotein profile, unlike tamoxifen, raloxifene
and toremifene do not induce uterine growth. Unfortunately, raloxifene causes an increase in hot flushes and
also increases the incidence of thromboembolic diseases.
Toremifene has not been in clinical use long enough to
yield sufficient follow-up data. However, the few safety
data that are accumulated suggest a favorable safety profile for toremifene (80).
B. Complete Blocking of Estrogen Signaling
There are two therapeutic strategies for completely
blocking estrogen signaling; one is the use of a pure ER
antagonist, having no agonistic properties, and the other
one is blocking of estrogen synthesis with the use of
aromatase inhibitors. Fulvestrant (ICI 182,780) binds, inhibits, and promotes degradation of ERs (47, 162). Preclinical studies have indicated that fulvestrant in combination with growth factor receptor inhibition is an effective treatment option for postmenopausal women with
advanced breast cancer. Because estrogen is essential for
maintenance of brain function, complete blocking of estrogen receptors may be associated with cognitive distur-
TABLE
1.
bances and may render neurons more sensitive to stress
and excitatory neurotoxins.
Aromatase inhibitors are effective in advanced breast
cancer, but clinical trials have indicated that resistance
develops with this strategy (reviewed in Ref. 40). Despite
intense research, optimal agents targeting ER signaling
have not yet been identified. Further investigation is likely
to increase our understanding of the complexities of ER
signaling and increase the chances of rational design of
more optimal ER ligands for targeting estrogen-dependent tumors.
C. Deleterious Effects of Anti-estrogens
The acquired tamoxifen resistance developed in tumors after some time of treatment is a major problem and
cause of serious concern to clinicians. Recent data indicate that growth factor signaling is likely to be involved in
the development of tamoxifen resistance. There is reciprocal cross-talk between estrogen and growth factor signaling: estrogens regulate growth factor signaling and
growth factors can activate ER (191, 257). The HER2
downstream signaling molecules ERK1 and ERK2 can
phosphorylate ER, leading to enhanced sensitivity of the
Coactivators reported to be involved in tamoxifen signaling
Gene Product
Mechanism of Activation
Involved ER Domain
Reference Nos.
AIB1
SRC-1
L7SPA
p68
Recruit HATs, NR boxes
Recruit HATs, NR boxes
Not known
Enhance tamoxifen activity when S118 phosphorylated, can recruit HATs
ER␣-AF-1 and LBD
ER␣-AF-1 and LBD
ER␣ hinge
ER␣-AF-1
2, 210, 311
263, 278
95
45
ER, estrogen receptor; LBD, ligand-binding domain; AF, activation function.
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ESTROGEN RECEPTOR SIGNALING
2. Estrogen receptor corepressors involved in
antagonist activity
TABLE
Gene Product
Mechanism of
Interaction
NCoR
SMRT
Class I
Class I
RTA
SAF B1/SAF B2
HDAC 4
SHP
NEDD 8
SAP 30
Class
Class
Class
Class
Class
Class
III
III
III
III or IV
III or IV
IV
Involved ER
Domain
ER␣-LBD
ER␣-LBD
ER␤-LBD
ER␣-AF1
ER␣-DBD
ER␣-AF1
Not known
Not known
Indirect
Reference Nos.
95, 98, 112, 134, 263
51, 95, 112, 263, 278
198
200, 202, 203, 295
136
116
47
81, 130, 186
Class I corepressors, CoRNR box recruitment motif; class III, lack
an identified interaction motif; class IV, indirect recruitment.
receptor to its cognate hormone and potentially to ligandindependent receptor activation (106). Interestingly,
ERK1/2 expression and activity are increased in several
estrogen nonresponsive human breast cancer cell lines
(30, 269). Coregulators are also subject to posttranslational modifications by the signaling kinases and thereby
these enzymes may indirectly affect ER activity (53, 85,
134, 322). Data from xenograft models and cell lines show
that overexpression of the growth factor receptor HER2
may constitute a primary mechanism of tumor resistance
to tamoxifen (13, 117, 170, 228). Recent clinical evidence
shows that patients with tumors expressing high levels of
the transcriptional coactivator AIB1 in combination with
HER2 have a poor response to tamoxifen. Those patients
with tumors expressing high HER2 or AIB1 separately had
a good disease-free survival (210). These data suggest that
increased growth factor signaling via HER2 activates kinases that lead to phosphorylation of ER and AIB1, circumstances under which the agonistic activity of tamoxifen might be enhanced (reviewed in Refs. 211, 256).
D. Structural Basis for ER Activity
Structural analysis of ER domains over the past decade has greatly enriched our understanding of receptor
function (232). While elucidation of the intact receptor’s
three-dimensional architecture continues to pose formidable challenges to structure determination techniques
due to interdomain flexibility and the poorly structured
nature of the NH2-terminal region, analysis of the individual DNA- and ligand-binding domains has provided a
wealth of information about sequence-specific DNA target
recognition (27, 114) and the ligand-induced conformational
changes that underpin receptor activation (188, 232).
The vast majority of structural studies of ER have
focused on its COOH-terminal LBD due to the desire to
develop subtype-specific ligands (115, 159). Consequently,
numerous crystal structures have been determined for the
Physiol Rev • VOL
917
LBDs of both ER subtypes bound to a range of different
ligands and coactivator fragments (see Table 3). These
studies have provided valuable information regarding the
structural basis of receptor agonism/antagonism and the
determinants that influence ER␣’s and ER␤’s ligand-binding preferences (229, 232). The crystal structures demonstrate that ligand binding to a buried cavity in the
interior of the ER-LBD stabilizes distinct receptor conformations that are subsequently interpreted by the
transcriptional apparatus.
One of the main weaknesses of crystal structure
analysis is that this technique typically provides a static
picture/snapshot of the molecules being analyzed. However, the sheer variety of complexes that have been determined for ER-LBD has allowed us to build a comprehensive dynamic picture of the characteristic structural
alterations that accompany binding of particular classes
of receptor ligands.
E. Role of Helix 12 in the Regulation
of AF-2 Activity
ER’s ligand-dependent transcriptional activation
function (AF-2) is localized in a conformationally dynamic region of the LBD. The key element of the AF-2
conformational switch is a short helical region (helix 12;
H12) located at the carboxy terminus of the LBD. Different classes of receptor ligands influence H12’s orientation
with respect to the rest of the LBD (Fig. 6). Agonist
ligands stabilize a receptor conformation that is optimal
for efficient interaction with coactivators and thereby
facilitates transcriptional activation. In such a “transcriptionally active” conformation, the helical elements that
comprise the AF-2 region (helices H3–5 and H12) assemble to form a shallow hydrophobic binding site for the
leucine-rich LxxLL motifs of NR coactivators (Fig. 6, A
and B). In this conformation, H12 is positioned across the
entrance to the ligand-binding pocket and constitutes a
key part of the coactivator docking surface (22, 195, 267).
In contrast, receptor antagonists interfere with positioning of H12 through a variety of mechanisms resulting in
ER conformations in which the coactivator recruitment
site is incomplete (Fig. 6, C–E).
In cases where H12 is not stabilized in the “agonist
conformation,” the helix is reoriented to bind along and
occlude the AF-2 groove (Fig. 6, C and D), thereby physically blocking the recruitment site (22, 267). The commonly held view is that H12 is able to bind along the
coactivator groove by mimicking the consensus LxxLL
motif with its own intrinsic related sequence (267). Our
recent analysis, however, suggests an alternate and more
compelling explanation: ER’s H12 region contains an
extended corepressor (CoRNR) box sequence that occludes the AF-2 site and prevents unwanted interaction
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TABLE
HELDRING ET AL.
3.
ER ligand-binding domain (LBD) crystal structures available from RCSB (November 2006)
Ligand
ER␣
E2
Ligand Class
Coregulator
Agonist
PDB Code*
Comments
IERE
IA52
SRC2-3
Cyclic LxxLL
IQKT
IQKU
IG50
IGWR
IPCG
DES
Agonist
mSRC2-2
JERD
RAL core
GEN
Agonist
Agonist
SRC2-2
SRC2-2
IGWQ
IX7R
THC
WAY-244
Agonist
Agonist
mSRC2-2
SRC2-2
IL21
1X7E
Benzopyran
Agonist
Oxabicyclophenols
Agonist
mSRC2-2
1ZKY/2BIV/2FAI
Dihydroequilenin
RAL
Agonist
Antagonist
mSRC2-2
2BIZ
1ERR
4-OHT
Antagonist
Affinity selected
peptide
JERT
210J
2BJ4
ER␤
Tetrahydro,
isoquinolines
GW56J8
Antagonist
IUOM/IXQC
Antagonist
IR5K
Dihydrobenzoxanthines
Antagonist
Chromanes
Aryl-naphthalene
Antagonist
Antagonist
ISJ0/IXP1/IXP6/
IXP9/IXPC
IYIM/IYIN
2AYR
E2
17-Epiestriol
Agonist
Agonist
NcoA5 peptide
NcoA5 peptide
2J7X
2JZY
ERB041
Agonist
SRC1-1
IX7B
WAY-J97
Agonist
SRC1-1
1U9E
WAY-697
Agonist
SRC1-1
1X76
WAY-244
Agonist
SRC1-1
1X78
CL-272
Agonist
SRC1-1
1O3Q
WAY-338
Agonist
SRC1-1
IU3R
WAY-297
Agonist
SRC1-1
1U3S
2-arylindene-1-one
Agonist
SRC1-1
1ZAF
2-Phenyl-naphthalene
Agonist
SRC1-1
1YY4/1YYE
Tetrahydrofluorenone
Agonist
2GIU
Benzopyran
Agonist
210G
Physiol Rev • VOL
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First structure of steroid receptor with
agonist
Intermolecular disulfide crosslink
generates nonphysiological
conformation of H12
Agonist conformation
Agonist conformation
Agonist conformation
Agonist conformation with CoA peptide
Complex with cyclic antagonistic LxxLL
peptide
First illustration of CoA recruitment with
LxxLL peptide bound along AF2
Agonist conformation
Agonist conformation. Provides clues to
origins of ER␣/␤ selectivity of GEN
Agonist conformation
Agonist conformation with ER␤ selective
agonist
Antagonist H12 conformation with ER␤
selective agonist
Agonist conformation with ER␤ selective
agonist based on oxabicylic scaffold
Agonist conformation
Complex with SERM highlighting
archetypal “antagonist conformation” of
H12 with AF2 groove occluded
Antagonist conformation
Complex with ER␣-specific phage-selected
peptide antagonist highlighting novel
putative coregulator docking site
ER␣ selective SERMs (SERAMs):
antagonist conformation
Antagonist conformation with orientation
of H12 that differs slightly from the
archetypal RAL/OHT structures
Series of ER␣-selective SERMs; antagonist
conformation
Series of ER␣-selective SERMs
Complex with SERM effective against
uterine leiomyoma
LxxLL-stabilized agonist conformation
Ligand orientation dictated by hydroxyl
positioning on D ring
Series investigating ER␤-selective agonist
binding
Series investigating ER␤-selective agonist
binding
Series investigating ER␤-selective agonist
binding
Series investigating ER␤-selective agonist
binding
Series investigating ER␤-selective agonist
binding
Series investigating ER␤-selective agonist
binding
Series investigating ER␤-selective agonist
binding
Series investigating ER␣/␤-selective
agonist binding
Series investigating ER␤-selective agonist
binding
ER␤-selective agonist; H12 bound along
AF2 in suboptimal orientation
H12 bound along AF2 in suboptimal
orientation with ER␤ selective agonist.
Binding mode
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Reference Nos.
22
44, 61
115
289
108
267
308
160
268
159
196
86
unpub
22
118
267
245, 246
19, 115
288
91
This study
This study
159
159
159
159
158
158
158
171
174
316
196
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ESTROGEN RECEPTOR SIGNALING
TABLE
3. —Continued
Ligand
GEN
Ligand Class
Coregulator
Partial agonist
SRC1-1
PDB Code
1QKM
1X7J
RAL
OHT
Antagonist
Antagonist
1QKN
2FSZ
Triazine
Antagonist
INDE
THC
Antagonist
1L2J
ICI 164.384
Full
Antagonist
1HJI
Comments
Reference Nos.
H12 bound along AF2 in suboptimal
orientation
Presence of LxxLL peptide forces H12 to
adopt classic agonist orientation
Antagonist conformation
Nonnative H12 orientation stabilized by
crystal contacts; additional OHT
molecule bound to AF2 cleft
ERb-selective SERM; antagonist
conformation
Antagonist conformation related to that
seen in 1QKM. First demonstration of
“passive⬙/indirect antagonism
Only pure antagonist structure; ICI side
chain sterically blocks both agonist and
antagonist docking of H12. AF2
accessible
160, 230
230
304
83
268
231
Coregulator peptide nomenclature is given as p160 subtype followed by NR box number. E2, 17␤-estradiol; DES, diethylstilbestrol; RAL,
raloxifene; OHT, 4-hydroxytamoxifen; THC, 5R-11R-diethyl-5,6,11,12-tetrahydrochrysene-5-ol; GEN, genistein; ER␤041, 2-(3-fluoro-4-hydroxyphenyl)-7vinyl-1, 3-benzoxozol-5-ol; ICI 164.384, (7␣,17␤)-n-butyl-3,17-dihydroxy-N-methyl-estra-1,3,5(10)triene-7-undecanamide. * Released PDB entries
(www.resb.org) as of November 2006.
with traditional NR corepressors (Heldring, unpublished
data). This would explain why removal of H12 greatly
enhances ER’s ability to interact with traditional NR corepressors such as NCoR and SMRT (89, 310).
F. Classical AF-2 Antagonism
The AF-2 antagonists tamoxifen/raloxifene (Fig. 6C)
and pure antagonist ICI 164,384 (Fig. 6E) all harbor a
bulky side chain of varying length that cannot be contained within the ligand-binding pocket. As a consequence, H12 is sterically hindered from aligning in the
proper agonist conformation. While tamoxifen and raloxifene are observed to induce similar receptor conformations, the rER␤-ICI structure (231) is slightly different
since ICI’s long alkylamido side chain itself binds along
the AF-2 recruitment site and completely abolishes the
association between H12 and the rest of the LBD
(Fig. 6E). Such differences in H12 positioning and concomitant AF-2 groove accessibility may underlie the pure
antagonist effects seen with ICI (189, 231). Subtle differences in the positioning and stabilization of H12 along
AF-2 may underlie the difference in tissue-specific actions
of certain anti-estrogens. For example, a recent structure
of hER␣ in complex with GW5638, an anti-estrogen that is
mechanistically distinct from raloxifene and 4-hydroxytamoxifen, exhibits a novel orientation for H12 along the
AF-2 binding groove (323).
It is worth noting that the structural snapshots provided by the various ligand complexes create a rather
false impression that the orientation of H12 is limited to a
few positions. This situation is exaggerated by the fact
Physiol Rev • VOL
that all structural studies have been carried out with the
isolated LBD, and we have little idea how other regions of
the receptor influence H12 dynamics. Instead, the “agonist” and “antagonist” states of H12 observed in the LBD
structures most likely represent stable end points in a
continuum of possible conformations that reflect the diverse agonist/antagonist character of ER ligands.
G. Nonclassical AF-2 Antagonism
AF-2 antagonism can also be achieved without a
bulky substituent (268). Such indirect antagonism occurs
when a ligand fails to make the appropriate contacts
within the ligand-binding cavity so that the antagonist
rather than the agonist orientation of H12 is preferred.
The crystal structure of hER␤ bound to genistein reveals
that even though genistein binds within the ligand pocket
in a similar manner to estrogen, H12 adopts an antagonist
position rather than the typical agonist position (230)
(Fig. 6D). The origin of this destabilizing effect on H12 is
unclear even though it is known that the agonist positioning of H12 is more unstable in ER␤ than in ER␣ possibly
due to altered residues at positions involved in anchoring
the NH2-terminal end of H12. The degree of destabilization appears to be marginal and the agonist orientation can be promoted by crystallizing ER␤-GEN in the
presence of an LxxLL peptide (160). In contrast, THC,
which acts as a full agonist on ER␣ while being a potent
antagonist on ER␤, strongly favors the antagonist H12
conformation when bound to ER␤. THC appears to
antagonize ER␤ by affecting key residues in the ligandbinding pocket that leads to the stabilization of tran-
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HELDRING ET AL.
scriptionally nonproductive conformations (268). These
findings provide key information for the rational design
of novel ER ligands with enhanced subtype selectivity
and diverse physiological effects. Yet another example
of nonclassical AF-2 antagonism may emerge from a
recent structure observation that 4-hydroxytamoxifen
occupies a second binding site on the ER␤ AF-2 surface
(304). If this weak-affinity nonvalidated binding site is
pharmacologically significant, antagonists might directly
interfere with receptor-coactivator interactions.
H. Coregulator Recognition of
Antagonist-Bound ER
As described above, coactivators (and in some cases
corepressors) are able to bind to the LBD conformation
stabilized by agonists via LxxLL motifs. However, receptor antagonists induce a conformation in which AF-2 exhibits little, if any, affinity for such motifs. It is well
established, at least for certain members of the NR superfamily, that the AF-2 region also serves as the docking site
for NR corepressors (87, 187, 224). In the case of antagonist-bound PPAR, the leucine-rich CoRNR box motif of
SMRT binds as an extended helix along the AF-2 binding
site (326). In the case of ER, the receptor conformation
induced by anti-estrogens such as raloxifene and 4-hydroxytamoxifen, in which AF-2 is completely occluded, is
difficult to reconcile with the known binding mode of the
CoRNR motif. Recently, we have determined the crystal
structures of two affinity-selected peptides, specific for
the 4-hydroxytamoxifen-bound receptor conformation, in
complex with the antagonist-bound ER␣ LBD (Heldring,
unpublished data). The two structures demonstrate that
the AF-2 region of ER is, in principle, capable of directly
TABLE
4.
interacting with corepressors. Both peptides bind along
the AF-2 region in a manner similar to the PPAR-SMRT
complex confirming that the general structural principles
of corepressor motif binding to AF-2 are conserved within
the NR superfamily. However, an internal CoRNR-box
sequence motif within H12 serves as an effective “corepressor surrogate” and provides a considerable barrier to
binding.
Alternatively, the AF-2 region may not serve as the
dominant protein-protein interaction site in the anti-estrogen-bound state, and putative ER cofactors may target
other alternative binding surfaces that are revealed in a
ligand-specific manner. Recently, we characterized one
such novel recruitment site for another phage-derived,
ER␣-specific interaction motif that lies on the opposite
face of the LBD (118). Whilst the question remains as to
whether this motif acts as a fortuitous conformational
probe or is an actual mimic of an ER interaction partner,
the docking site on the surface of ER appears to be a bona
fide control surface involved in regulating receptor
activity.
I. ER Coregulators
Studies in the past decade have provided much novel
information on the general and cell-type specific actions
of distinct coregulators involved in chromatin remodeling, histone modifications, transcription initiation and
elongation, splicing, and coordinated degradation. Most
of these proteins are bona fide coregulators for many
members of the NR family and have been studied extensively using ERs (reviewed in Refs. 146, 223, 279; see also
http://www.nursa.org). Coregulators are recognized to be
critical for proper function of ER signaling in development, reproduction, and physiology, and alterations in
Estrogen receptor corepressors which decrease estrogen stimulatory effects
Gene Product
Mechanism of Interaction
Involved ER Domain
Reference Nos.
LCoR
SHP
RIP 140
DAX-1
MTAIs
DP97
REA
MTA1
BRCA1
LIM domain only 4
Smad4
MRF-1
pp32
CtBP
HER2/neu
SHARP
Class II
Class II
Class II
Class II
Possibly class II
Class III
Class III
Class III
Class III
Class III
Class III
Class III
Class III
Class IV
Class IV
Class IV
ER␣-LBD
ER␣-LBD ER␤-LBD
ER␣-LBD
ER␣-LBD ER␤-LBD
ER␣-AF1, AF2, and DBD
ER␣-LBD
ER␣-LBD
ER␣-LBD
ER␣-LBD
ER␣-DBD and LBD
ER␣-AF1
ER␣-AF1 and LBD
ER␣-DBD
Indirect
Indirect
Indirect
48
99
23
131, 329
124
241
34, 273
123, 169, 192
156, 330
277
142
64
147
7, 300
126, 210
265
Class II, LxxLL recruitment motif; class III, lack an identified interaction motif; class IV, indirect recruitment.
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ESTROGEN RECEPTOR SIGNALING
coregulator function and expression are associated with
cancer and other diseases.
The best-defined structure-function coregulator interaction is with the steroid receptor coactivator SRC
(p160) family of coactivators. The important role of the
p160 family members in ER signaling has been demonstrated with loss of function studies where ER activation
is heavily affected, and severe phenotypes have been
observed in estrogen target tissues when p160s are absent
(63, 325). Interestingly, increased expression of AIB1
(SRC-3) has been observed in breast tumors, suggesting
a possible involvement in carcinogenesis (2). However,
many other proteins are also involved in ER signaling.
Coactivators and corepressors have been shown to exist in multifunctional protein complexes (81, 88, 261,
292, 328). Even though the components of several complexes are identified, less is known about the processes
controlling the recruitment by transcription factors.
One model suggests that distinct coactivator and corepressor complexes are present in a preformed state and
are recruited to the transcription site depending on the
state of the transcription factor/NR/ER (65, 81). However,
some coactivators and corepressors are, despite their
opposite function, found in the same protein complexes
(4, 143, 178, 287, 297).
With regard to corepressors, a number of recent
studies have demonstrated that both agonist- and antagonist-bound ERs are able to recruit a variety of proteins
that apparently repress activity (Tables 2 and 4). Simplified, these putative ER corepressors can be grouped
into four major classes based on the reported interaction mechanisms (Fig. 7): those that contain a classical
corepressor (CoRNR-box; class I) interaction motif
(263), those that contain an LxxLL motif and are recruited in an estrogen-dependent manner acting as anticoactivators (class II) (23, 48, 116, 329), those with less
defined interaction mechanisms but most likely different from NR/CoRNR box type of interactions and possibly including an interaction-domain outside LBD
(class III) (34, 47, 64, 124, 142, 169, 198, 203, 241, 330),
and those that have indirect effects and possibly are
recruited via complexes (class IV) (130, 210, 265, 300).
However, the possibility also exists that some corepressors are recruited through multiple independent mechanisms and therefore would qualify to belong to several
classes. For example, small heterodimer partner (SHP)
FIG. 7. Schematic representation of ER corepressors based on the reported interaction mechanism.
Class I: corepressors interacting through classical
CoRNR-box motifs. Class II: corepressors interacting
through NR boxes, thereby blocking coactivator binding. Class III: corepressors that most likely display
interactions different from NR and CoRNR-box type.
Class IV: corepressors with indirect effects possibly
recruited via complexes.
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HELDRING ET AL.
has been shown, in addition to acting as an anti-coactivator (class II) in an estrogen-dependent manner, also
to repress the agonist activity of tamoxifen (116), and
this function is most likely achieved through a different
mechanism of recruitment. Several of the corepressors
shown to affect estrogen signaling may have the potential to be involved in antagonist signaling as well, provided that their mechanisms of repression are not due
to anti-coactivator function by occupying the hydrophobic NR box site.
basis of anti-estrogen signaling which is invaluable for the
development of more selective and effective ER ligands
and for future improvements of clinical applications.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence:
J.-Å. Gustafsson, Dept. of Biosciences and Nutrition, Karolinska
Institutet, Novum, SE-141 57 Huddinge, Sweden (e-mail:janake.gustafsson@mednut.ki.se).
GRANTS
V. CONCLUDING REMARKS
The writing of this review coincides with a heated
debate about the clinical use of estrogens and anti-estrogens provoked by the results of two large epidemiological
studies, the Women’s Health Initiative (WHI) investigating
the pros and cons of hormone replacement therapy (HRT)
and the Early Breast Cancer Trialist’s Collaborative
Group (EBCTG). It is clear that an understanding of the
multifaceted estrogen receptor signaling is important
from both a preclinical and a clinical perspective. A combination of interdisciplinary efforts including cell and molecular biology and genetically modified animals has generated a solid platform of knowledge but has also provided the basis for future research directions in the field.
Much research effort has been focused on how ERs, in the
absence of estrogens, can be activated by growth factor
pathways and what the relevance of this phenomenon is
to development of anti-estrogen resistance in cancer. The
fact is that ER␣ and ER␤ are modulators of growth factor
pathways, and if this modulation is lost, growth becomes
dependent solely on growth factors and their receptors. In
this review we have discussed how estrogen influences
growth factor pathways. It is a complex interaction between epithelium and stroma, depending on the changing
presence of ER␣ and ER␤ in these two tissue compartments. Current evidence suggests a cell-type specific involvement of coregulators in determining transcriptional
activities of antagonist-bound ERs. However, molecular
details of how antagonists trigger recruitment of these
suggested coregulators remain unknown. One of the important issues for the future is to identify and characterize
the proteins that bind or communicate with ERs in the
presence of antagonists. It is likely that the currently
known coregulators only represent a fraction of those
mediating receptor activities. Considering that the two
ERs appear to have overlapping but also unique biological
functions, it is most likely that receptor subtype-specific
coregulators exist. Identification of new coregulators may
provide novel targets for development of new classes of
therapeutic drugs with potential use in the treatment of
diseases involving ER signaling. In this review we have
discussed the advances in understanding the molecular
Physiol Rev • VOL
Some of the research discussed in this review was supported by grants from the Swedish Cancer Research Fund,
Swedish Research Council, KaroBio AB, and the European Commission funded network of Excellence CASCADE.
DISCLOSURES
J.-Å. Gustafsson is share holder and consultant of KaroBio AB.
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