PHYSIOLOGICAL REVIEWS
Vol. 81, No. 4, October 2001
Printed in U.S.A.
Mechanisms of Estrogen Action
STEFAN NILSSON, SARI MÄKELÄ, ECKARDT TREUTER, MICHEL TUJAGUE, JANE THOMSEN,
GÖRAN ANDERSSON, EVA ENMARK, KATARINA PETTERSSON, MARGARET WARNER,
AND JAN-ÅKE GUSTAFSSON
KaroBio AB and Departments of Biosciences and of Medical Nutrition, Karolinska Institute, NOVUM;
Department of Pathology, Huddinge Hospital, Huddinge, Sweden; and Institute of Biomedicin
Department of Anatomy, University of Turku, Turku, Finland
Introduction
Estrogen Receptor Types ␣ and ␤ Structure and Functional Domains
Estrogen Receptor Splice Variants
Specific Estrogen Receptor Types: ␣ and ␤ Ligands
Estrogen Receptor-DNA Interactions
Phosphorylation of Estrogen Receptors
A. Ligand binding and ER phosphorylation
B. Non-estrogen-dependent activation of ER
C. Cyclins as activators of ER
D. Outcome of phosphorylation on ER function
E. Phosphorylation of ER␤
VII. Transcriptional Cofactors: Coactivators, Negative Coregulators, and Corepressors
A. Cofactors and ER agonism
B. The p160/SRC coactivator family
C. CBP/p300: coactivators and SRC-associated acetyltransferases
D. The TRAP/DRIP coactivator complex
E. Unique coactivators with possible relevance for ERs
F. Negative coregulators and corepressors
G. Corepressors
H. Non-AF-2 interacting coactivators
I. Differences between ER␣ and ER␤ with regard to cofactor recruitment
J. Cofactors and cancer
VIII. Estrogen Receptor-Aryl Hydrocarbon Receptor Interactions
A. Antiestrogenic effects of AhR ligands
IX. Estrogen Receptor-Related Receptors: Interplay With Estrogen Receptors
X. Tissue Distribution of Estrogen Receptor Type ␤
XI. Estrogen Action and Estrogen Receptor Type ␤ in the Male
A. Expression of ERs and estrogen action in testis and epididymis
B. Expression of ERs and estrogen action in male accessory sex glands
C. Estrogens and prostatic disease
D. Expression of ERs and estrogen action in lower urinary tract
XII. Estrogen and the Mammary Gland
XIII. Role of Estrogen Receptors in Bone
XIV. Evolution of Nuclear Receptors
A. ERs in fish
XV. Concluding Remarks
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Nilsson, Stefan, Sari Mäkelä, Eckardt Treuter, Michel Tujague, Jane Thomsen, Göran Andersson, Eva
Enmark, Katarina Pettersson, Margaret Warner, and Jan-Åke Gustafsson. Mechanisms of Estrogen Action.
Physiol Rev 81: 1535–1565, 2001.—Our appreciation of the physiological functions of estrogens and the mechanisms
through which estrogens bring about these functions has changed during the past decade. Just as transgenic mice
were produced in which estrogen receptors had been inactivated and we thought that we were about to understand
the role of estrogen receptors in physiology and pathology, it was found that there was not one but two distinct and
functional estrogen receptors, now called ER␣ and ER␤. Transgenic mice in which each of the receptors or both the
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0031-9333/01 $15.00 Copyright © 2001 the American Physiological Society
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NILSSON ET AL.
receptors are inactive have revealed a much broader role for estrogens in the body than was previously thought. This
decade also saw the description of a male patient who had no functional ER␣ and whose continued bone growth
clearly revealed an important function of estrogen in men. The importance of estrogen in both males and females
was also demonstrated in the laboratory in transgenic mice in which the aromatase gene was inactivated. Finally,
crystal structures of the estrogen receptors with agonists and antagonists have revealed much about how ligand
binding influences receptor conformation and how this conformation influences interaction of the receptor with
coactivators or corepressors and hence determines cellular response to ligands.
I. INTRODUCTION
II. ESTROGEN RECEPTOR TYPES ␣ AND ␤
STRUCTURE AND FUNCTIONAL DOMAINS
ER␣ and ER␤ belong to the steroid/thyroid hormone
superfamily of nuclear receptors, members of which
share a common structural architecture (99, 118, 123, 166,
218, 363). They are composed of three independent but
interacting functional domains: the NH2-terminal or A/B
domain, the C or DNA-binding domain, and the D/E/F or
ligand-binding domain (Fig. 1). Binding of a ligand to ER
triggers conformational changes in the receptor and this
leads, via a number of events, to changes in the rate of
transcription of estrogen-regulated genes. These events,
and the order in which they occur in the overall process,
are not completely understood, but they include receptor
dimerization, receptor-DNA interaction, recruitment of
FIG. 1. Diagramatic representation of the domain structure of nuclear receptors. The A/B domain at the NH2 terminus contains the AF-1 site where other transcription factors interact. The C/D domain contains the two-zinc finger
structure that binds to DNA, and the C/F domain contains
the ligand binding pocket as well as the AF-2 domain that
directly contacts coactivator peptides.
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More than 30 years ago Jensen and Jacobsen (156)
came to the conclusion, based on the specific binding of
estradiol-17␤ (E2) in the uterus, that the biological effects
of estrogen had to be mediated by a receptor protein. For
24 years this protein was extensively studied in several
laboratories (57, 120), and in 1986, two groups reported
the cloning of this estrogen receptor (ER) (121, 122). Until
1995, it was assumed that there was only one ER and that
it was responsible for mediating all of the physiological
and pharmacological effects of natural and synthetic estrogens and antiestrogens. However, in 1995, a second
ER, ER␤, was cloned from a rat prostate cDNA library
(182). The former ER is now called ER␣. Since then,
several groups have cloned ER␤ from various species (93,
242, 352, 355, 358) and have identified several ER␤ isoforms (67, 208, 221, 240, 257, 271). The discovery of ER␤
has forced a reevaluation of the biology of estrogen and,
because of the abundance of ER␤ in the male urogenital
tract, has refocused attention on the role of estrogen in
males.
and interaction with coactivators and other transcription
factors, and formation of a preinitiation complex (27, 28,
166, 176, 177, 228, 291, 322).
The N-terminal domain of nuclear receptors encodes
a ligand-independent activation function (AF1) (30, 177,
224, 356), a region of the receptor involved in proteinprotein interactions (226, 259, 384), and transcriptional
activation of target-gene expression. Comparison of the
AF1 domains of the two estrogen receptors has revealed
that, in ER␣, this domain is very active in stimulation of
reporter-gene expression from a variety of estrogen response element (ERE)-reporter constructs, in different
cell lines (78), but the activity of the AF1 domain of ER␤
under the same conditions is negligible. Another striking
difference between the two receptors is their distinctive
responses to the synthetic antiestrogens tamoxifen, raloxifene, and ICI-164,384. On an ERE-based reporter gene,
these ligands are partial E2 agonists with ER␣ but are
pure E2 antagonists with ER␤ (23, 223, 227). Dissimilarity
in the NH2-terminal regions of ER␣ and ER␤ is one possible explanation for the difference between the two receptors in their response to various ligands. In ER␣, two
distinct parts of AF1 are required for the agonism of E2
and the partial agonism of tamoxifen, respectively (223).
In ER␤, this dual function of AF1 is missing (227). The
importance of ER␤AF1 in transcriptional activity therefore remains to be clarified.
The DNA binding domain (DBD) contains a two zinc
finger structure, which plays an important role in receptor
dimerization and in binding of receptors to specific DNA
sequences (27, 95, 128a, 128b, 315, 367). The DBDs of ER␣
and ER␤ are highly homologous (93). In particular, the P
box, a sequence which is critical for target-DNA recognition and specificity, is identical in the two receptors (371).
Thus ER␣ and ER␤ can be expected to bind to various
EREs with similar specificity and affinity.
The COOH-terminal, E/F-, or ligand-binding domain
(LBD) mediates ligand binding, receptor dimerization, nuclear translocation, and transactivation of target gene
MECHANISMS OF ESTROGEN ACTION
higher affinity for ER␤. When genistein is bound to ER␤,
helix 12 does not adopt an agonist conformation but has,
instead, a position more similar to that seen with an
antagonist. This result is unexpected because the molecular shape and volume of genistein and E2 are very similar
(274) and because genistein is a partial (60 –70% of E2)
agonist with ER␤ on an ERE-driven reporter gene (23).
There is no explanation at present for the conformation of
helix 12 in the ER␤-genistein structure. It may well be that
there are subtle conformational differences between the
two ER subtypes that are not discerned by comparing
their primary amino acid sequences or crystallographic
tertiary structures. Agonists induce conformations of ER
that promote and stabilize ER-coactivator interaction
(357) while ER-coactivator interaction reciprocally stabilizes ER-ligand interaction, markedly slowing the rate of
dissociation of bound agonist from both ER␣ and ER␤ in
vitro (115). Clearly, further structural studies with ERligand complexes are required to fully understand the
subtle interrelationship between ligand binding and helix
12 orientation.
III. ESTROGEN RECEPTOR SPLICE VARIANTS
Several splice variants of ER␤ have been described.
Some have extended NH2 termini, and others have truncations and/or insertions at the COOH terminus and in the
LBD. A human ER␤ cDNA encoding a protein of 530
amino acids was identified in 1998 (256). It was longer
than the original rat ER␤ clone, and this difference was
due to an NH2-terminal extension, composed of 45 amino
acids. Later, a rodent ER␤ isoform that was 64 amino acid
residues longer than the original rat ER␤ clone (ER␤-485)
FIG. 2. Crystal structure of the ligand binding
domain of type ␤ estrogen receptor (ER␤) in the
presence of an agonist (genistein) and an antagonist
(raloxifene). The picture depicts the two distinct positions of helix 12 which are adopted with the two
ligands. (Photograph courtesy of KaroBio and Rod
Hubbard, University of York.)
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expression (99, 118, 363). Amino acid residues that line
the surface of the ligand binding cavity, or that interact
directly with bound ligands, span the LBD from helix 3 to
helix 12 (44, 274, 356). The LBD also harbors activation
function 2 (AF2), which is a complex region whose structure and function are governed by the binding of ligands
(83, 84, 102, 133, 216, 321). Crystallographic studies with
the LBDs of ER␣ and ER␤ revealed that the AF2 interaction surface is composed of amino acids in helix 3, 4, 5,
and 12 and that the position of helix 12 is altered by
binding of ligands. When the ER␣ LBD is complexed with
the agonists, E2 or diethylstilbestrol (DES), helix 12 is
positioned over the ligand-binding pocket and forms the
surface for recruitment and interaction of coactivators
(44, 321, 398). In contrast, in the ER␣- and ER␤-LBD
complexes with raloxifene (44, 274) or the ER␣-LBD
4-OH-tamoxifen complex (321), helix 12 is displaced from
its agonist position over the ligand-binding cavity and
instead occupies the hydrophobic groove formed by helix
3, 4, and 5. In this position, helix 12 foils the coactivator
interaction surface (Fig. 2). It is evident that different
ligands induce different receptor conformations (223,
264) and that the positioning of helix 12 is the key event
that permits discrimination between estrogen agonists
(E2 and DES) and antagonists (raloxifene and 4-OH-tamoxifen).
The LBDs of ER␣ and ER␤ share a high degree of
homology in their primary amino acid sequence and are
also very similar in their tertiary architecture. It is, therefore, not surprising that the majority of compounds tested
so far bind to ER␣ and ER␤ with similar affinities (183) or
have similar potencies in activation of ERE-mediated reporter gene expression (23). The phytoestrogen genistein
is one naturally occurring ligand that has an ⬃30-fold
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and perhaps also dysfunction, is ER␣ and -␤ gene polymorphisms. ER␣ polymorphisms have been linked to increased litter size in pigs (300, 325), breast cancer susceptibility (4, 313, 411), bone mineral density and
osteoporosis (169, 236, 260), hypertension (201), spontaneous abortion (203, 311), and body height (202).
IV. SPECIFIC ESTROGEN RECEPTOR TYPES:
␣ AND ␤ LIGANDS
The discovery of ER␤ has revitalized the search for
improved tissue-selective estrogen receptor modulators
(SERM). Such ligands could provide the benefits of estrogens and avoid unwanted side effects of E2. In the clinical
setting, these pharmaceuticals would be used for prevention or treatment of menopausal symptoms, osteoporosis,
cardiovascular disease, and breast cancer in women, or
other estrogen-related indications affecting both men and
women (72, 74, 124, 245, 287). Several large pharmaceutical companies are engaged in the development of ER␣and ER␤-selective SERMs, but none has yet come to
market. Katzenellenbogen and co-workers (230, 346) have
synthesized ER subtype-specific ligands. The most ER␣selective ligand had a 120-fold higher agonist potency for
ER␣ than for ER␤. Another selective ligand showed full
ER␣ agonism but pure ER␤ antagonism (346). The ER␤selective antagonist was further investigated by the synthesis of a series of analogs with substituents of various
sizes in both cis- and trans-configurations (230). All analogs were agonists on ER␣, but only those with small
substituents were ER␤ agonists. As substituent size increased, the agonism on ER␤ disappeared, and with larger
substituents the ligands were pure ER␤-selective antagonists. The gradual ER␤-selective antagonism by this series
of analogs was influenced by both size and shape of the
substituent. It was concluded by the authors that less
steric perturbation is required to induce an antagonist
conformation in ER␤ than in ER␣ This could be due in
part to the observation (274) that the volume of the
binding cavity of ER␤ is smaller than that of ER␣.
Are phytoestrogens natural SERMs? Phytoestrogens
are nonsteroidal polyphenolic compounds present in several edible plants. On the basis of their chemical structure, phytoestrogens may be divided into four subclasses:
isoflavonoids, flavonoids, coumestans, and mammalian
lignans. The major dietary source of isoflavonoids (e.g.,
genistein, daidzein, formononetin, biochanin A) is soybean. Flavonoids (e.g., chrysin, apigenin, naringenin,
kaempferol, quercetin) are more widely distributed in the
plant kingdom and are present in several edible plants.
Coumestans (e.g., coumestrol) are present in plants not
commonly used in human diets, such as alfalfa sprouts.
Mammalian lignans (e.g., enterolactone and enterodiol)
are not present in human diets as such, but are ingested as
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was reported (208). In addition to extensions of the NH2
terminus, three groups have reported cloning of ER␤-503,
an isoform with an in-frame insertion of 18 amino acids in
the LBD (67, 128, 271). This isoform is a splice variant,
and the insert is in the junction between exons 5 and 6
(93). In contrast to the NH2-terminally extended ER␤
isoforms, the affinity of ER␤-503 for E2 and other known
ER ligands is lower than for ER␣ and for ER␤-485. In one
report, ER␤-503 acted as a dominant negative regulator by
suppressing E2-dependent ER␣- and ER␤-mediated activation of gene transcription, but did not bind E2 (221). In
other reports, ER␤-503 did exhibit E2-dependent transcriptional activation of a reporter gene, but the concentration of E2 needed was 100- to 1,000-fold higher than
that for ER␣ (271, 128). All ER␤ isoforms, 503, 485, and
530, bind to consensus ERE and heterodimerize with each
other and with ER␣ (128, 271).
Transcripts encoding additional ER␤ isoforms with
variations at the extreme COOH terminus have been
found in human testis cDNA libraries (257, 240). ER␤cx
(257) is identical to ER␤-530 in exons 1–7, but exon 8 is
completely different. The last 61 COOH-terminal amino
acids (exon 8), encoding part of helix 11 and helix 12,
have been replaced by 26 unique amino acid residues. Due
to the exchange of the last exon, ER␤cx lacks amino acid
residues important for ligand binding and those that constitute the core of the AF2 domain. It is, therefore, not
surprising that ER␤cx does not bind E2 and has no capacity to activate transcription of an E2-sensitive reporter
gene (257). Surprisingly, in view of its intact DBD, ER␤cx
does not bind to a consensus ERE. Furthermore, ER␤cx
shows preferential heterodimerization with ER␣ rather
than with ER␤, inhibiting ER␣ DNA binding. Functionally,
the heterodimerization of ER␤cx with ER␣ has a dominant negative effect on ligand-dependent ER␣ reportergene transactivation (257).
Moore et al. (240) have described five ER␤ isoforms
(ER␤ 1–5). ER␤ 1 corresponds to the previously described ER␤-530 (256), and the ER␤ 2 variant is most
likely identical to ER␤cx (257). However, ER␤ 3–5 are
novel splice variants with exchanges of the last exon of
ER␤-530 for previously unknown exons. As with ER␤cx,
neither of the novel COOH-terminal splice variants, ER␤
3–5, can be expected to bind E2 or activate transcription
from an ERE-driven reporter, as they all lack amino acids
important for ligand binding as well as the core of AF2. In
contrast to what was reported for ER␤cx (257), two of the
COOH-terminal splice variants, ER␤ 2 and 3, do bind to a
consensus ERE.
Various alternatively spliced forms of ER␣ have also
been described (108 –110, 243, 351, 406). To date there is
insufficient information as to whether or not all isoforms
and splice variants of ER␣ are expressed as proteins or
whether they have any major biological and physiological
role. Another source of variability in receptor function,
MECHANISMS OF ESTROGEN ACTION
V. ESTROGEN RECEPTOR-DNA INTERACTIONS
For several years it was thought that the only mechanism through which estrogens affected transcription of
E2-sensitive genes was by direct binding of activated ER
to EREs. These estrogen response elements were first
observed in the 5⬘-flanking region of the Xenopus vitelPhysiol Rev • VOL
logenin A2 gene (168). Today we know that ER␣ and ER␤
can also modulate the expression of genes without directly binding to DNA (Fig. 3). One example is the interaction between ER␣ and the c-rel subunit of the NF␬B
complex. This interaction prevents NF␬B from binding to
and stimulating expression from the interleukin-6 (IL-6)
promoter (112). In this way, E2 inhibits expression of the
cytokine IL-6 (112, 292). Another example of indirect
action on DNA is the physical interaction of ER␣ with the
Sp1 transcription factor (25, 277, 289). ER␣ enhancement
of Sp1 DNA binding is hormone independent (277), and
both ER␣ and ER␤ can activate transcription of the retinoic acid receptor ␣1 (RAR-1) gene, presumably by the
formation of an ER-Sp1 complex on GC-rich Sp1 sites in
the RAR1 promoter (345, 409). Interestingly, in one study,
ER␤ activated RAR-1 promoter-reporter constructs in the
presence of the estrogen antagonists 4-OH-tamoxifen,
raloxifene, and ICI-164,384. E2 did not activate expression of the reporter but blocked the effect of the antagonists (409).
Both ER␣ and ER␤ can interact with the fos/jun
transcription factor complex on AP1 sites to stimulate
gene expression, however, with opposite effects in the
presence of E2 (264, 383, 385). In the presence of ER␣,
typical agonists such as E2 and DES as well as the antiestrogen tamoxifen function as agonists in the AP1 pathway. Raloxifene is only a partial agonist. In contrast, in
the presence of ER␤, tamoxifen and raloxifene behave as
fully competent agonists in the AP1 pathway, while E2
acts as an antagonist, inhibiting the activity of both tamoxifen and raloxifene (264). Analysis of the mechanism
of ER␣-stimulated expression from an AP1 site showed
that agonist-bound ER␣ requires intact AF1 and AF2 functions and that it enhances AP1 activity via interactions
with the p160 family of coactivators. In this “agonist”
pathway the DBD of ER␣ is essential. The “antiestrogen”
pathway, triggered by antiestrogen-liganded ER␤, enhances AP1 activity in an AF1- and AF2-independent fashion but also requires an intact DBD. The DBD sequesters
corepressors from the AP1 transcription complex, releasing it from suppression and subsequently resulting in
AP1-dependent transcription (385).
The electrophilic/antioxidant response element
(EpRE/ARE) is yet another site on DNA where ER␣ and
ER␤ behave differently. In MCF-7 cells, antiestrogens but
not E2 activate transcription of the quinone reductase
gene and increase NAD(P)H:quinone oxidoreductase enzyme activity via an EpRE/ARE (239). Furthermore, E2
inhibits the agonistic effect of the antiestrogens on EpRE/
ARE reporter constructs, and in this capacity, ER␤ is
more efficacious than ER␣ (238). These findings suggest
that antiestrogens are antioxidants and inducers of phase
2 detoxification enzymes, protecting cells from damage by
oxygen radicals and other toxic by-products of metabolic
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precursors (plant lignans), which are converted to mammalian lignans by gut microflora. Plant lignans are present
in fiber-rich foods, such as flaxseeds and unrefined grain
products. Isoflavones and coumestrol interact with ER in
vitro, although the activities of individual compounds
with similar chemical structures vary remarkably (23,
183). Some flavonoids show modest estrogenic activity,
while others are completely inactive (183). Mammalian
lignans are very weak estrogens, and concentrations of
1 mM or more are required to show any ER␣- or ER␤mediated activity (303, 308).
It has been suggested that dietary genistein could
play a role in preventing the development of hormonedependent diseases and conditions, such as breast and
prostate cancer, cardiovascular disease, menopausal
symptoms, and osteoporosis (reviewed in Ref. 341). This
suggestion comes from epidemiological studies, showing
an inverse correlation between the intake or serum concentrations of genistein and the risk of estrogen-related
diseases and conditions. At present, there is no direct
evidence for the beneficial action of genistein in humans.
It has also been claimed that genistein would be devoid of
the adverse effects typically found with E2, but this has
not been shown convincingly either.
There are very little data from in vivo studies to
demonstrate the tissue and/or ER␤ selectivity of genistein
that has been demonstrated in vitro (23). Most studies
have been done with high doses of genistein, likely to
exert both ER␣- and ER␤-mediated activities. Furthermore, careful dose-response studies have not been done.
In most in vivo studies, genistein acts as an estrogen and
induces effects similar to E2 in female and male experimental animals (308, 340). At low doses, genistein and
other isoflavones have been shown to act selectively in
the cardiovascular system. In female macaques, isoflavones have favorable effects on the cardiovascular system
without affecting the reproductive tract (7). In female
rats, genistein was as potent a vasculoprotectant as E2,
but unlike E2 showed no uterotrophic activity (216a). At
present, it is not known to what extent the vascular
responses are mediated by ERs. Both ER subtypes are
expressed in vascular tissues, but in addition, there is
sufficient evidence to indicate the presence of non-receptor-mediated actions of E2 in the same tissues. Further
studies are thus needed to demonstrate that genistein acts
in a receptor- or tissue-selective manner in vivo.
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oxidation. Furthermore, it would seem that these protective effects of antiestrogens are mediated by ER␤.
Another potentially important pathway of estrogen
action is constituted by the very rapid, so-called, nongenomic effects of certain ligands (232). There is evidence
that some of the rapid effects of nuclear receptor ligands
require the presence of the receptor protein (237, 266,
293). In endothelial cells, E2-mediated membrane effects
lead to sequential activation of ras, raf, mitogen-activated
protein kinase kinase (MEK), and subsequently activation
of mitogen-activated protein kinase (MAPK) (71). It has
been suggested that this leads to activation of endothelial
nitric oxide synthase (eNOS) and release of nitric oxide
(NO). In neurons, membrane effects of estrogen lead to
stimulation of src, ras, MEK, and MAPK, resulting in
neuroprotection, and in osteoblasts the membrane effects
of estrogen may be involved in control of apoptosis, cell
proliferation, and differentiation (71).
VI. PHOSPHORYLATION OF ESTROGEN
RECEPTORS
During the past 15 years, the dogma of the strict
requirement of hormones for activation of steroid recepPhysiol Rev • VOL
tors has been challenged. Evidence for ligand-independent activation of these receptors through alternative signaling pathways has emerged (reviewed in Refs. 55, 91,
386, 387). In most instances, the mechanisms underlying
this activation involve phosphorylation of the receptors
(318, 386). The phosphorylation sites on native ER␣ from
calf, mouse, and rat uterus, and from human MCF-7 cells,
have been extensively studied by analysis of the phosphoamino acid content of the receptor and/or its binding
to anti-phosphotyrosine antibodies (21, 22, 233) There are
still several controversial issues such as whether both
tyrosine and serine are phosphorylated and which phosphorylations are ligand dependent. Some investigators
report phosphorylation on tyrosine (3, 22, 231, 233) while
others detect serine as the only phosphorylated amino
acid (13, 51, 85, 191). A single tyrosine phosphorylation
site in human ER␣ at position 537 has been identified in
vitro (12) and in vivo (11, 12, 14). Whether or not this
phosphorylation is E2 dependent is still a point of contention (14).
Phosphorylation of ER␣ on serine residues has been
studied with recombinant human or mouse ER␣ expressed in COS-1 cells in the presence of E2 (190, 200).
The vast majority of phosphoserine residues were
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FIG. 3. Model representing the various modes through which estrogen receptors can modulate transcription of genes.
In the first panel is depicted the classical interaction of the activated receptor with estrogen response elements (EREs)
on DNA. In the other three panels are representations of the indirect effects of estrogen receptors on transcription
interactions. This occurs through protein-protein interactions with the Sp1, AP1, and NF␬B proteins.
MECHANISMS OF ESTROGEN ACTION
A. Ligand Binding and ER Phosphorylation
Even though ER␣ is phosphorylated in the absence
of E2 in different cell lines (12, 200), enhanced phosphorylation of the receptor occurs in response to physiological
doses of E2 (3, 16, 85, 200). E2 treatment of MCF-7 cells
has also been reported to result in the dephosphorylation
of a single unspecified site in ER␣ (11). The enzymes
responsible for E2-dependent phosphorylation of ER
seem to be diverse. They include an E2-dependent tyrosine kinase, which has been purified from calf uterus
(52), and a casein kinase II in MCF-7 cells, which phosphorylates Ser-167 (11). In addition, serines other than
Ser-167 are E2-stimulated phosphorylation sites (3, 158,
159, 200) that do not have casein kinase II binding sites in
their environment (157a), and this suggests other novel
and (so far) unspecified kinases.
B. Non-estrogen-dependent Activation of ER
In the absence of E2, other signaling pathways can
modulate ER through phosphorylation. These include
1) regulators of the general cellular phosphorylation
state, such as protein kinase A (PKA) (16, 46, 153) or
protein kinase C (PKC) (152, 267, 189, 200); 2) extracellular signals such as peptide growth factors, cytokines, or
neurotransmitters (56); and 3) cell cycle regulators. Peptide growth factors represent a large class of ER activators. Epidermal growth factor (EGF) can mimic the effects of E2 in the mouse reproductive tract, and
pretreatment of mice with the pure anti-estrogen ICI164,384 greatly diminishes the uterine response to EGF
(151). In line with this cross-talk between ER␣ and EGF,
Physiol Rev • VOL
mice in which ER␣ has been inactivaed (ERKO mice) lack
uterine E2-like response to EGF even though the EGF
signaling pathway is not disrupted (82). Other growth
factors which activate ER␣ signaling include insulin (249,
267, 268), insulin-like growth factor I (IGF-I) (16, 152, 215,
249), and transforming growth factor (TGF)-␤ (152).
In all of these cross-couplings between growth factors and ER␣, the mediators are the guanine nucleotide
binding protein p21ras and the MAPK (46). p21ras functions as an intermediate between the membrane-associated growth factor receptor/tyrosine kinase and MAPK
phosphorylation cascades. The target site of these kinases
on ER␣ has been mapped to the AF-1 domain. In most
studies, this target has been further localized to Ser-118 in
hER␣, which corresponds to the consensus phosphorylation site for MAPK (46, 165). However, it appears that
there are alternative pathways of cross-coupling between
growth factors and ER. For example, in the SK-N-BE
neuronal cell line, the target for the insulin activation of
ER␣ has been mapped to the AF-2 region (267). This
observation suggests that different mediators of the
growth factor signal, downstream of p21ras, might be involved. In line with this hypothesis, EGF activation of ER
in endothelial cells of the pulmonary vein is independent
of MAPK and does not involve the same phosphorylation
site in ER␣ (164). Furthermore, the 90-kDa ribosomal S6
kinase, pp90rsk1, a serine/threonine protein kinase which
is phosphorylated by MAPK upon EGF stimulation, phosphorylates Ser-167 in hER␣ (158).
Other extracellular signals that can modulate ER activity are heregulin (273), interleukin-2 (IL-2), and dopamine (279, 334). Dopamine is, so far, the only neurotransmitter identified as an ER activator. Dopamine activation
of ER is distinct from activation by EGF, since a mutant
hER␣, which is no longer activated by dopamine, can still
be activated by EGF (15, 114). The mechanisms involved
in ER activation by IL-2 or by dopamine remain elusive,
and it has not yet been shown whether phosphorylation of
the receptor is involved. Phosphorylation is clearly involved in heregulin activation of ER. In breast cancer
cells, activation, by heregulin, of the heregulin receptor,
HER-2 (a tyrosine kinase), leads to direct and rapid phosphorylation of ER on tyrosine residues, followed by transcription of the progesterone receptor gene. Heregulin
promotes hormone-independent growth in human breast
cancer cells, and overexpression of HER-2 results in the
development of E2-independent growth, which is insensitive to both E2 and tamoxifen.
C. Cyclins as Activators of ER
Cyclins are positive regulatory subunits of cyclindependent kinases (CDKs), a class of serine/threonine
kinases that are major determinants in cell cycle progres-
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mapped to the NH2-terminal A/B domain. Outside of this
domain, sites have been identified at positions 236 in the
DBD, 294 in the hinge region, and 305 in the LBD (numbering here refers to the position in the human sequence).
Within the A/B domain, Ser-104, -106, -118, -154, and -167
were characterized as phosphorylation sites in human
ER␣ (hER␣) in the presence of E2 (160, 200). In the
mouse ER␣ (mER␣), three phosphoserine residues were
clearly mapped in the A/B domain at positions 122, 156,
and 158 (190). The precise location of the fourth phosphorylation site remains unsettled. It could correspond
either to Ser-171 or to Ser-522. There is a high degree of
homology between hER␣ and mER␣, and all identified
phosphoserines but one are conserved in these receptors
(Fig. 3). Moreover, not only are the serine residues preserved at these positions, but their environments are well
conserved too. The unique exception is position 156,
which is Ser in mER␣ and proline in hER␣. There is still
disagreement about the importance of phosphorylation of
Ser-104, -106, and -167 in hER␣ (3, 13, 190, 200).
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NILSSON ET AL.
D. Outcome of Phosphorylation on ER Function
All of the steps in transcriptional activation of ERdependent genes, i.e., ligand binding, ER dimerization,
DNA binding, and the interaction with cofactors, appear
to be influenced by phosphorylation of ER. Ligand binding
of ER␣ is regulated by phosphorylation of Tyr-537 (10,
231, 233). The dimerization function of ER␣ appears to be
enhanced by phosphorylation at Ser-236 in the DBD (62)
and its DNA binding capacity by phosphorylation at Ser167 (11, 51, 85). MAPK-mediated phosphorylation at Ser118 in ER␣ potentiates the interaction with the coactivator p68 (92).
E. Phosphorylation of ER␤
In contrast to the numerous studies related to ER␣
phosphorylation, only one group has so far investigated
ER␤ phosphorylation (357). This study demonstrated
phosphorylation of recombinant ER␤ when it was expressed in human embryonic kidney cells (293 T). The
target sites for EGF-induced phosphorylation of ER␤ are
two serine residues located at positions 106 and 124 in
consensus sequences for MAPK. Despite a poor overall
homology between ER␣ and ER␤ in the A/B domain,
Ser-106 is part of a motif shared with ER␣ and other
steroid receptors and corresponds to Ser-118 in human
ER␣. Phosphorylation at Ser-106 and -124 enhanced the
interaction with the coactivator SRC-1 (357).
VII. TRANSCRIPTIONAL COFACTORS:
COACTIVATORS, NEGATIVE
COREGULATORS, AND COREPRESSORS
Current models of eukaryotic gene regulation suggest the existence of distinct gene activity states i.e.,
repressed/silenced, basal/ ground state, and activated
states (342, 343). Estrogen signaling is usually associated
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with gene activation, i.e., the switch between basal and
activated state. As cellular environments change, ERs can
associate with distinct subsets of cofactors depending on
binding affinities and relative abundance of these factors
(66, 125). Coactivators turn on target gene transcription,
while negative coregulators and corepressors inhibit gene
activation and possibly also turn off activated target
genes. These proteins exist in multiple complexes, possess multiple enzymatic activities, and (in a simplified
view) bridge ERs, to either chromatin components such
as histones, to components of the basal transcription
machinery, or to both. During the past 5 years, proteinprotein interaction screenings and biochemical approaches have led to identification of a large number of
cofactors which may act at different functional levels (for
current review, see Refs. 107, 142, 229, 396, 397, 400). The
majority of these cofactors bind to the LBD, which (as
described above) plays a central role not only in binding
of ligands but also in transforming the ligand signal. So
far, only very few receptor-specific cofactors have been
identified, and the various nuclear receptors appear to
utilize similar cofactors.
A. Cofactors and ER Agonism
Although all ER ligands bind exclusively to the LBD,
binding of an agonist triggers AF-2 activity, but binding of
antagonists does not. As described above, structural analyses of ER complexed with E2 or raloxifene/tamoxifen
show that each class of ligand induces a different LBD
conformation (44, 274, 321). These structural rearrangements are critical for ligand-induced transcriptional regulation, since it is the exposed surface of the receptor that
recruits coactivators and other coregulatory proteins.
Some characteristic AF-2 cofactors with relevance for
agonist-bound ERs are illustrated in Figure 4. They can be
categorized in several subgroups.
B. The p160/SRC Coactivator Family
This well-characterized coactivator family consists of
three related members (reviewed in Ref. 228): SRC-1, the
first identified nuclear receptor coactivator and founding
member of the family (also p160 –1, N-CoA1); SRC-2 (also
TIF-2, GRIP1, N-CoA2); and SRC-3 (also P/CIP, ACTR,
AIB1, RAC3, TRAM1). Critical for the function of these
coactivators is the central nuclear receptor-interaction
domain consisting of three equally spaced conserved
LXXLL motifs, also called NR-box or LCD/LXD (reviewed
in Ref. 400). These motifs represent the primary docking
sites to the AF-2 domain and exist in many different
cofactors (199). With regard to ERs, it has been found
that, in the case of SRC-1 and -2, the second motif (NRbox 2) has the highest affinity for the agonist-bound ER␣
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sion. The activities of many proteins, including transcription factors, are modulated by CDKs. Because CDKs
control cell division, dysregulation of their regulatory
partners, the cyclins, has been implicated in the initiation
and promotion of hyperplasia and oncogenesis (380, 389).
Two different cyclins, cyclin A and D1, have been identified as ER activators (247, 280, 361, 412). Individual overexpression of these proteins elicits an increase of ER
activity in the absence of E2. Distinct mechanisms seem
to mediate the activation of ER by these two cyclins.
Cyclin D1 activation of ER does not involve a phosphorylation, since it does not require participation of a CDK
(361, 412, 247), but cyclin A does activate ER by a phosphorylation in the AF-1 domain (296, 361).
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MECHANISMS OF ESTROGEN ACTION
(i.e., the AF-2 domain), while in SRC-3, the first motif
serves as primary docking site (66, 344). Recent ER␣
costructures with a single NR-box 2 peptide have visualized the interactions of the NR-box with the AF-2 domain
(322). It is hoped that, in the future, costructural analysis
of the entire SRC interaction domain including all three
NR-boxes with dimeric ERs will be possible. An additional COOH-terminal region in SRC-1 has been implicated in binding to the NH2-terminal ER␣ AF-1 domain
(140, 214, 384). This offers an interesting explanation for
the collaboration of receptor NH2 and COOH termini in
activation, which is exhibited by ER␣ but not ER␤.
All SRC coactivators contain two separate transcription activation domains, AD-1 and AD-2. AD-1 is involved
in recruitment of CBP/p300 coactivators and acetyltransferases and AD-2 in recruitment of a second proteinmodifying enzyme called coactivator-associated arginine
methyltransferase (CARM1) (61). The COOH termini of
SRC-1 and SRC-3 exhibit intrinsic lysine acetyltransferase
activity. Together with evidence for the existence of histone acetyltransferase (HAT) complexes consisting of
SRC, CBP/p300, and/or PCAF/GCN5 (400), these features
strongly indicate that SRC coactivators function primarily
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by recruiting chromatin (i.e., histone)-modifying enzymatic activities to ligand-activated nuclear receptors and,
thereby, to hormone-regulated target genes. Additionally,
acetylation of lysine residues adjacent to the core of
NR-box1 in SRC-3 abolishes the interactions with the
AF-2 domain of ER␣ and may represent one important
mechanism for attenuation and feedback regulation in
estrogen-regulated gene expression (64). A role for SRC
coactivators in ER-mediated gene expression and, possibly in carcinogenesis, is suggested by the discovery of
frequent AIB1 gene amplification in ER-positive breast
and ovarian cancer cells (8) as well as by the phenotype
of SRC-1 knock-out mice (399).
C. CBP/p300: Coactivators and SRC-Associated
Acetyltransferases
CBP/p300 are viewed as general coactivators and
cointegrators involved in multiple signaling pathways.
They are ubiquitously expressed, possess acetyltransferase activity, and contain docking sites for ERs, via
NH2-terminal NR-boxes. Several studies have highlighted
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FIG. 4. Structural organization of cofactors with relevance for agonist-bound
ERs. Highlighted are the nuclear receptor
(NR) interaction domains with conserved
LxxLL motifs, transcription activation domains (AD) and their potential target factors (CBP, ADA2, TBP), as well as potential DNA-binding domains.
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D. The TRAP/DRIP Coactivator Complex
A large coactivator complex, referred to as TRAP/
SMCC/DRIP/ARC complex, may connect ERs directly to
the basal transcription machinery (155, 107). The complex was first identified biochemically from HeLa cells
using the thyroid-hormone receptor (155 and references
therein). The receptor-binding subunit of the entire
complex, referred to as TRAP220 (TRIP2/PBP/DRIP205/
RB18A), has been isolated independently in several laboratories using two-hybrid screenings. It is not known
whether the two complexes act sequentially or independently on nuclear receptors (107, 155). It has been suggested, however, that acetylation of the AF-2 NR-box
binding motif could be one possible mechanism for dissociation of the SRC coactivators from ERs, allowing
other cofactor complexes such as TRAP/DRIP to bind
(64). ER␣ is less efficient than ER␤ in recruiting the
TRAP/DRIP complex in vitro (228), and this may indicate
differences in the physical interaction of the ER subtypes
with coactivator complexes.
E. Unique Coactivators With Possible Relevance
for ERs
Additional unique coactivators exist that are structurally distinct from CBP/p300, p160/SRC, or TRAP/DRIP proteins. However, functional connections to ERs have not yet
been made for these cofactors. Examples are 1) NSD1, a
bifunctional coactivator and corepressor containing a SET
domain, a motif found in several chromatin-modifying proteins (146); 2) TIF1, which exhibits or associates with protein kinase activity and probably connects receptors with
other chromatin components such as the heterochromatin
protein HP1 and the SNF-2 component of the mammalian
SWI/SNF-complex (106, 197, 294); 3) the PPAR␥ coactivator
PGC-1, which interacts with ERs probably via its NR-box
motif and which exists in a complex with SRC-1 (254, 285,
Physiol Rev • VOL
286); and 4) a novel coactivator called ASC-2/RAP250 (48,
198). This coactivator contains one functional NR-box motif,
is widely expressed in many tissues (48), and appears to be
overamplified or overexpressed in certain cancers (198). It is
currently not known whether ASC-2/RAP250 functions separately or in conjunction with other coactivator complexes.
F. Negative Coregulators and Corepressors
Studies on several additional ER cofactors illustrate
that not all AF-2 binding proteins act simply as coactivators. Two AF-2 interacting proteins, RIP140 and SHP
(short heterodimerization partner) (see Fig. 5), exhibit
negative coregulatory functions, because they can antagonize SRC-1 coactivators in vivo and compete for AF-2
binding in vitro (53, 161, 359, 360). Therefore, these cofactors may belong to a separate category of coregulators
that are distinct from conventional corepressors. SHP is a
remarkable and unusual orphan receptor that has a recognizable LBD but lacks a DBD (161, 162, 316). Both SHP
and its closest relative DAX-1 interact with several nuclear receptors and inhibit their transcriptional activity
(79, 316, 317). SHP binds directly to the AF-2 domain of
ERs via two separate NR-box motifs and thus functions in
the same way as AF-2 cofactors (161, 162). SHP mRNA is
widely expressed in rat tissues including certain estrogen
target tissues, and subcellular localization studies demonstrate that SHP is a nuclear protein. Under some circumstances ER may associate with corepressors utilizing SHP
or DAX-1 as bridging proteins. This may recruit corepressors/deacetylases to ER target genes and thus antagonize
acetyltransferase/coactivator complexes.
G. Corepressors
The related “conventional” corepressors N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid receptors), associate with ER␣
in the presence of antagonistic ligands (reviewed in Ref.
228), and it has been suggested that they may play a role
in regulating ER activity in tumors treated with antiestrogens (335). There is evidence that histone deacetylase
activity recruited by corepressor complexes such as
N-CoR/SAP30/SIN3/HDAC2 is required for the transcriptional repression of tamoxifen-bound ER␣ (188, 194, 335).
Lavinsky et al. (194) have observed that acquisition of
tamoxifen resistance in MCF-7 cells growing in athymic
nude mice (a model of human breast cancer) is accompanied by a decrease in corepressor levels. They suggest
that loss of corepressors may be one mechanism of tamoxifen resistance.
Because direct binding of antagonist-bound ER to
corepressors has not been demonstrated, indirect recruitment mechanisms are also possible. In view of the in-
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their involvement in ER activation (127, 176), but it is yet
unclear whether they bind directly to ERs under physiological conditions, i.e., in the presence of other competing
coactivators. Instead, affinity considerations (407) and the
existence of multiple interactions between CBP/p300 and
other acetyltransferases argue for a scenario in which SRC
coactivators are required for the recruitment of CBP/p300 to
receptors. In support of a critical role of CBP/p300 in histone
acetylation, studies utilizing receptors other than ERs have
shown that CBP HAT activity was required for efficient
target gene activation in vivo (175). Possibly, the requirement for multiple ER-associated HATs may also reflect the
partially different substrate specificity (histones and nonhistone targets) of these enzymes. The role of CBP/p300 on
ER␤ functions has not yet been studied.
MECHANISMS OF ESTROGEN ACTION
1545
sights gained from the structure of antagonist-bound ERs
(44, 274, 321) and from corepressor interactions with
retinoic acid, thyroid, and ecdysone receptors (405, 145,
362, 405), it is likely that ER antagonists, via the realignment of helix 12 and possibly the F-domain (251), expose
as yet unidentified corepressor binding epitopes.
In a yeast two-hybrid screen with a dominant negative ER␣ as bait, a novel corepressor was recently identified (238). This factor also repressed the agonist activity
of both ER subtypes (but not that of other receptors) by
competitive reversal of SRC-1 enhancement. The cofactor
was named REA for “repressor of estrogen receptor activity.” REA may, therefore, represent a bivalent cofactor
with corepressive functions on both estrogen- and antiestrogen-bound ERs. Another candidate corepressor is
the RSP5/RPF1 protein, which specifically represses the
tamoxifen-mediated partial agonist activity of ER␣ (255).
bound progesterone receptor as bait in yeast two-hybrid
screenings, and subsequently demonstrated also to bind and
enhance the agonistic properties the tamoxifen-bound ER␣
(349). The hinge domain has been mapped as interaction site
on PR, and it is likely that L7-SPA recognizes features that
are conserved between antagonist-bound steroid receptors.
In this respect, L7-SPA shares interaction features with corepressors, and this lends support to the idea that part of its
function is competitive antagonism of corepressor function.
As mentioned below, identification of synthetic peptides,
which interact specifically with the antagonist-bound ER,
suggest that there could be multiple sites on ER where
coactivators in cells could interact only when the receptor is
bound to an antagonist.
I. Differences Between ER␣ and ER␤ With Regard
to Cofactor Recruitment
H. Non-AF-2 Interacting Coactivators
Although the involvement of corepressors in antagonist
signaling may in part explain their antiestrogenic activity in
breast cancer treatment, it is not easy to envisage how
corepressors alone account for the agonistic activites of
antiestrogens. The existence of novel coactivators that bind
to ERs only in the presence of antagonists has been postulated, and a few candidates have been identified. One such
coactivator, called L7-SPA, was identified using RU487Physiol Rev • VOL
One major unanswered question is whether or not ligand-bound ER␣ and ER␤ contact different coactivators/
cofactors. Because of the homology in their AF-2 domains, it
was anticipated that the two ER subtypes would be similar
in coactivator recruitment, but certain differences have been
reported. For example, affinity of the ER␣ interaction with
SRC-3 is much higher than that observed for the ER␤ (344),
and in contrast to ER␣, ER␤ apparently interacts in a ligandindependent manner with SRC-1 and SHP in vitro (78, 317,
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FIG. 5. Model illustrating the interplay
between coactivators and coregulators/corepressors in estrogen signaling. The model
may in part apply for antagonist signaling,
yet the individual coregulator components
such as coactivators for tamoxifen-bound
ERs remain to be identified.
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NILSSON ET AL.
J. Cofactors and Cancer
Although no cause and effect relationship between cofactors and carcinogenesis has been established, gene amplification and overexpression of the ER coactivators SRC-3,
AIB3/ASC-2/RAP250, and TRAP220/PBP have been found in
breast and ovarian cancer (8, 198, 408). Additionally,
changes in the expression levels of conventional corepressors, which associate with antagonist-bound ERs, may contribute to the phenomenon of tamoxifen resistance in breast
cancer treatment. There could, for example, be imbalances
or changes in the ratio between corepressors and coactivators (194). Interestingly, ER␣ and SRC-1 are coexpressed in
stromal cells but not in epithelial cells in the mammary gland
(324). The response of the stroma to E2 differs from that of
the epithelium, perhaps indicating that association between
ERs and different coactivators may influence the responsiveness to E2. Lately, it has been suggested that transcriptional cross-talk between ERs and other major players in
breast cancer such as BRCA1 or cyclin D1 occurs at the
cofactor level via ligand-independent recruitment of acetyltransferases (100, 229). Although it is currently not known
whether cofactor levels are related to carcinogenesis, it
seems likely that changes in the levels or activity of cofactors could have profound effects on target gene expression.
Such changes may shift the balance from differentiation to
proliferation and contribute to the development of neoplastic diseases.
VIII. ESTROGEN RECEPTOR-ARYL
HYDROCARBON RECEPTOR
INTERACTIONS
More than two decades ago, it was first reported that
ligands for the aryl hydrocarbon receptor (AhR) can counPhysiol Rev • VOL
teract the effects of estrogens in intact animals (173). Like
ER, AhR is a ligand-inducible transcription factor, but in
contrast to ER, an endogenous ligand has yet to be identified. AhR is a member of the bHLH/PAS class of transcription factors, members of which are involved in development,
oxygen homeostasis, and circadian rhythm (for review, see
Ref. 80). AhR is the only ligand-activated bHLH/PAS protein
identified, and because the majority of ligands are classified
as environmental contaminants, AhR functions as a toxin
sensor. Ligands for AhR include environmental polycyclic
aromatic hydrocarbons (PAHs), 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD) (275), related polychlorinated dibenzo-pdioxins (PCDDs) and dibenzofurans (PCDF) (for review, see
Ref. 276), and dietary indole carbinols present in cruciferous
vegetables (35, 41, 65, 373). After ligand binding, AhR is
found in the cell nucleus as a heterodimer with the AhR
nuclear translocator Arnt (139). The AhR-Arnt heterodimer
binds to specific genomic enhancer sequences termed dioxin- or xenobiotic-responsive elements (DREs or XREs),
and this interaction leads to transcriptional activation.
Those genes that are transcriptionally activated as a result of
AhR interactions with 5⬘-upstream DREs have been described as members of the Ah gene battery and include
phase I drug-metabolizing enzymes such as cytochromes
P-450IA1 (CYP1A1), CYP1A2, and CYP1B1 and phase II enzymes including glutathione-S-transferase Ya subunit, UDP
glutathione transferase, aldehyde dehydrogenase, and
NAD(P)H quinone oxidoreductase (NQOR) (for review, see
Ref. 126). In addition to the Ah battery, a number of E2regulated genes (see below) are regulated by AhR at either
the transcriptional or posttranscriptional level.
A. Antiestrogenic Effects of AhR Ligands
In vivo, the most distinct antiestrogenic effects of
TCDD in rodents are decreased uterine weight (113, 304),
reduction in the incidence of mammary and uterine cancer (41, 172, 173), and inhibition of E2 induction of PR,
EGF receptor, and c-fos protooncogene in immature or
ovariectomized rodent uterus (18, 19, 297). In humans,
accidental exposure to TCDD, as occurred in 1979 in
Seveso, has resulted in a decrease in mammary and endometrial cancer (31, 32). In vitro, several genes have
been identified as targets for cross-talk between ER and
AhR. Among E2-regulated genes that are affected by
TCDD treatment are cathepsin D (180), pS2 (402), prolactin receptor (211), c-fos (87, 88), hsp27 (278), TGF-␣ and
TGF-␤ (111), as well as PR (129). E2-induced cell proliferation and postconfluency production of foci are also
decreased by TCDD (34, 116, 390).
TCDD is not a typical ER antagonist, because it does
not compete with E2 for binding to ER (130). Instead,
ligands for AhR might mediate their antagonistic effects
on ER signaling by several separate pathways. These
include the following.
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357). Furthermore, as mentioned above, the TRAP/DRIP
complex apparently binds only weakly to ER␣.
Such differences may be associated with distinct binding specificities of the NR-box interaction motifs (84, 216,
225). Clearly, preferential binding of certain coactivators to
one of the ERs should have consequences for E2 signaling.
In addition, because there are differences in the ligandbinding specificities of the two ERs, and because ligands can
alter receptor conformations, ligand-binding specificity is
likely to affect cofactor binding affinities and specificity.
Indeed, such differences in receptor conformation have
been found by an affinity-selection approach. This method
was used to select peptides that specifically bound to ER
subtypes in the presence of agonists or antagonists (255,
265). These experiments clearly showed that different agonists and antagonists induce different ER conformations,
which in turn result in the recruitment of different ERbinding peptides.
MECHANISMS OF ESTROGEN ACTION
Physiol Rev • VOL
IX. ESTROGEN RECEPTOR-RELATED
RECEPTORS: INTERPLAY WITH
ESTROGEN RECEPTORS
The estrogen receptor related receptors ␣ and ␤
(ERR␣, ERR␤) were first identified based on their amino
acid identity to ER␣ (118). The ERRs constitute a subgroup of orphan receptors that are evolutionarily and
functionally most closely related to the steroid receptor
subfamily of nuclear receptors, in particular the ERs (192,
193). These receptors display similarity to the ERs particularly in the DBD (⬎65% amino acid identity), and to a
lesser extent in the LBD (⬃35% identity), but they do not
bind estrogen or estrogen-like compounds. To date, three
different members of this family have been identified,
ERR␣ and ERR␤ (initially named ERR-1 and -2, Ref. 118)
and recently, an ERR␥ of human origin, probably ortologous to an ERR-3 (63, 98, 141).
Expression pattern analysis has revealed a structurally and temporally restricted expression of ERR␤ during
mouse embryo development. Essentially expression is
confined to trophoblast progenitor cells in the developing
chorion between day 6.5 and 7.5 days postcoitum (dpc).
These structures eventually form the placenta (272), so it
is not surprising that mice, homozygous for a targeted
disruption of the ERR␤ gene, die during early embryogenesis due to placental failure (213). In adult tissues, ERR␤
expression levels appear to be low, and it is found only in
a few organs (118, 272). ERR␣, in contrast, displays a
more ubiquitous expression in adult tissues (118, 323,
333). During mouse embryogenesis, expression of ERR␣
can be detected at day 8.5 in extra embryonic tissues,
apparently sequential in time to expression of ERR␤, and
also in the primitive heart. ERR␣ expression is further
detected from 10.5 dpc in the heart of the embryo and
later at 13.5 dpc in skeletal muscle. At later stages, expression of ERR␣ is detected in a number of tissues
including adipose tissue and central nervous system (38,
39). Finally, although only a limited number of reports are
available, ERR␥ appears to be expressed in several adult
and fetal tissues, in particular brain and kidney (63, 98,
141).
In addition to the structural similarities between ER
and ERR, there are also certain functional similarities.
ERRs activate transcription from ERE-containing reporter constructs (141, 370, 371) and interact with heat
shock protein 90 (Hsp90) (272). Hsp90 is part of a chaperone system, which is involved in signal transduction of
a variety of hormone and growth factor receptors (reviewed in Ref. 281).
ERR␣ and ERR␤ also bind to DNA sequences that are
the recognition site for binding of the nuclear receptor,
steroidogenic factor-1 (SF-1), which is known to bind to
DNA as a monomer. The sequence (TCA AGG TCA) is
known as an SFRE. Surprisingly, the ERRs bind prefer-
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1) The first pathway is by increasing the rate of
metabolism of E2. TCDD increases the degradation of E2
by inducing CYP1A1 and CYP1B1, enzymes involved in
the metabolic inactivation of estrogens (131, 304, 337, 338,
397a).
2) The second pathway is by decreasing levels of
ERs. In vitro experiments have shown that TCDD treatment of MCF-7 human breast cancer cells and mouse
hepatoma (Hepa 1c1c7) cells resulted in a dose-dependent decrease in levels of ER␣. There was no decrease
in ER in Hepa cells expressing a mutated AhR (130,
403). In vivo, TCDD suppressed ER␣ mRNA by 60% in
an AhR-responsive mouse strain (C57BL/J6), but not in
DBA/2J mice, a nonresponsive strain (353). Both the
ER␣ (390) and ER␤ (unpublished observations) genes
contain DREs in their 5⬘-flanking regions. In addition to
transcriptional regulation of ER, downregulation of ER
by TCDD may be achieved by changes in receptor
synthesis, recycling, and/or degradation, as is the case
in mammary carcinoma cell lines where TCDD treatment decreases the level of ER protein by a proteasome-dependent pathway (304).
3) The third pathway is by suppressing transcription
of E2-induced genes. As discussed above, ER can interact
with DNA at ERE, Sp1, and AP-1 sites. A consensus DRE
sequence has been identified that confers the antiestrogenic effect of liganded AhR complex on several genes.
This inhibitory DRE (iDRE) has the core sequence
GCGTG, which binds the AhR complex. In the cathepsin
D gene (379), an iDRE lies between the ERE-half site and
the Sp1 site in the ERE/SpI motif, disrupting the formation of the ER␣/Sp1-DNA complex (347). In the fos gene,
liganded ER␣ does not bind directly to DNA, but to DNAbound Sp1. In this case an iDRE juxtaposes the Sp1 site,
suggesting competition between Sp1 and AhR for DNA
binding (87, 88). In the pS2 gene an iDRE overlaps the
AP-1 site in the ERE/AP-1 motif (54, 402), and in the hsp27
gene an iDRE is located 100 bp downstream of the ERE/
Sp1 motif close to the transcription start site, probably
blocking access of the basal transcription machinery to
the promoter (278).
4) The fourth pathway is by competing for shared
cofactors. AhR interacts with various factors in the
basal transcription complex (250, 301, 397a), including
TATA-binding protein and transcription factor IIF
(TFIIF) and TFIIB (347), whereas Arnt makes contact
with TFIIF and CBP (170). Coactivators and corepressors might be involved not only in regulation of AhR,
but also in cross-talk mechanisms between AhR and
ER. Thus RIP140 (185, 210a), ERAP140, SMRT (250),
and SP-1 protein (171) are involved in both AhR- and
ER-mediated transcription and represent sites where
the two receptors might compete.
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X. TISSUE DISTRIBUTION OF ESTROGEN
RECEPTOR TYPE ␤
In rodents, the tissues with the highest expression
levels of ER␤ are the prostate, ovary, and lungs, all tissues
where, in the past, the mechanism of action of estrogen
was difficult to understand because of the low content of
ER␣. Not surprisingly, therefore, these are the tissues that
exhibit very pronounced dysfunction in ER␤ knock-out
mice (BERKO) (179). ER␤ is also present in mammary
glands, bone, uterus, central nervous system, and cardiovascular system, tissues which also express ER␣. Because
the two estrogen receptors may influence each other’s
functions, estrogen action in tissues where they are coexpressed is very complex, and when one of the receptors
is deleted, the resulting changes in physiological functions can be difficult to interpret. Recent reviews have
covered estrogen actions in the central nervous system
(184), cardiovascular system (101), and ovary (381), and
these tissues are not discussed in this review.
XI. ESTROGEN ACTION AND ESTROGEN
RECEPTOR TYPE ␤ IN THE MALE
There is ample evidence for pronounced effects of
exogenous E2 exposure in the developing and adult male
Physiol Rev • VOL
urogenital tract. However, it has not been clear to what
extent these effects are due to direct E2 actions mediated
via ERs in reproductive tissues. Direct actions have to be
distinguished from indirect effects, which are caused by
actions of E2 on the hypothalamic-pituitary-gonadal axis
and result in insufficient androgen production. Until 1995,
because of the paucity of ER␣ expression in the male
urogenital tract, it was thought that the effects of E2 were
indirect. This view changed when ER␤ was found to be
widely expressed in developing and adult male urogenital
tract of several animal species (42, 135, 136, 182, 205, 284,
299, 310, 326, 374). Phenotypes of mice lacking functional
ERs, or aromatase, clearly indicate that lack of E2 action
results in structural and functional alterations in the male
reproductive system (86, 89, 295, 330), and it has become
obvious that the role of direct E2 action in the urogenital
tract needs to be critically reevaluated.
A. Expression of ERs and Estrogen Action
in Testis and Epididymis
In the testis, both ER␣ and ER␤ are expressed, but
the expression profiles of these two receptors are different. In rodent testes, ER␣ is localized in the nuclei of the
Leydig cells (104), while ER␤ is found in germ cells,
Sertoli cells, and fetal Leydig cells (299, 310, 374). In the
excurrent ducts of adult male rats, both ER␣ and ER␤ are
expressed (105, 136). Very little is known about the expression of ER proteins in the human testis. At early
stages of gonadal development (during the first trimester), no ER protein was detected in spermatogonia or
their supporting cells (290). However, midgestational human fetal testis expresses high levels of ER␤ mRNA and
small quantities of ER␣ mRNA (42). Human spermatozoa
and adult testis express ER␤ mRNA (132, 212). In fact,
multiple ER␤ transcripts have been detected in human
testis (240, 256). In situ hybridization studies show that
ER␤ mRNA is localized in developing spermatids, while
germ cells at earlier stages of differentiation, Sertoli cells,
and Leydig cells are negative (93). A similar expression
pattern for ER␤ was observed in immunohistochemical
studies with biopsy samples from young infertile men
with obstructive azoospermia (217). Strong immunoreactivity for ER␤ was detected in nuclei of the spermatogonia, spermatocytes, and early developing spermatids. No
reaction was seen in elongating spermatids or mature
spermatozoa, Sertoli cells, or Leydig cells. Furthermore,
no ER␣ was observed in any of the samples. Because of
the difficulty in obtaining age-matched biopsies from normal males, it is not yet known whether this distribution of
ERs in the testis is normal or is related to infertility.
In situ synthesized E2 appears to play a crucial role in
normal testicular and epididymal function. Multiple cell
types in testis, as well as in the excurrent ducts, including
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entially as homodimers to both the SFRE and to EREs
(368). ER␣, but not ER␤, can bind to SFREs and can
activate transcription from SFRE reporter constructs, a
feature that represents the first functionally discriminatory difference of DNA target recognition between the
two ERs (371). A number of studies have demonstrated
that ERR␣ can activate transcription of aromatase, lactoferrin, osteopontin, thyroid hormone receptor ␣, and human medium-chain acyl coenzyme A dehydrogenase
genes (332, 368, 369, 375, 401). Furthermore, ERR␣ participates in regulation of the simian virus 40 (SV40) major
late promoter (393, 410). No ligand has yet been identified
for the ERRs, but transcriptional activity of ERR␣ is
dependent on a serum factor that is present in culture
media. This factor can be removed from serum by treatment with dextran-coated charcoal, and activity can be
restored by addition of untreated serum. These data suggest that the serum factor may be a true ligand for ERR␣
(370). In contrast, ERR3 appears to be constitutively active in vitro (141). The ability of the ERRs to activate
transcription of ERE containing genes must be of pharmacological concern, particularly during therapeutic use
of anti-estrogens. Anti-estrogenic compounds such as ICI164,384 do not interfere with the action of ERRs (370) so
that during antiestrogen therapy ERRs are free to activate
ERE-regulated genes. The extent to which such transcriptional action can affect the outcome of antiestrogen therapy remains to be investigated.
MECHANISMS OF ESTROGEN ACTION
Physiol Rev • VOL
latation of rete testis and seminiferous tubules; impaired
spermatogenesis; reduction in Leydig cell number and
size; reduction in testicular androgen production; and
dose-dependent alterations in Sertoli cell number, germ
cell volume, and germ cell apoptosis (2, 20, 105, 319). In
some studies, in utero exposure of human males to DES
was reported to cause developmental abnormalities similar to those described in laboratory animals (33, 339).
However, the evidence is not conclusive, and in other
studies, no reproductive abnormalities were found in sons
of DES-treated women (195, 235, 392). The role of gonadal
ERs in mediating the effects of E2 during development is
not yet clear. It is not known to what extent these effects
are due to reprogramming of the central nervous system
and/or altered gonadotropin secretion. Studies with ER
knock-out animals will be helpful in understanding the
mechanisms responsible for the immediate as well as the
long-term effects of exposure to E2 during development.
B. Expression of ERs and Estrogen Action in Male
Accessory Sex Glands
In adult male rodents, E2 induces structural and
functional changes in both epithelial and stromal compartments in the accessory sex glands (29, 196, 222, 269,
309). In the prostate and seminal vesicles, some of the
changes (e.g., the castration-like involution) are indirect
and mediated via the central nervous system-gonadal
axis, but it is apparent from experiments with castrated
animals and with organ cultures that E2 may also act
directly on the prostate (24, 103, 220, 222, 246, 309). ER␣
is present only in few cells in the prostate, mainly in
stromal cells of the prostatic lobes and the posterior
periurethral region. Epithelial cells are devoid of or contain very low levels of ER␣ (73, 282, 287). In adult animals,
the effects of E2 on the central nervous system-gonadal
axis are pronounced. It causes reduced androgen production and rapid involution of accessory sex glands. The
direct actions of E2 in accessory sex glands, particularly
the prostate, are stimulatory and/or growth promoting,
but these effects are difficult to observe, in vivo, as they
are usually masked by the castration-like effect of E2. In
castrated rodents, the most notable changes caused by
administration of E2 are growth of fibromuscular stroma,
development of squamous epithelial metaplasia in ejaculatory and prostatic collecting ducts, infiltration of inflammatory cells, induction of the expression of c-fos protooncogene, and increased production of a major prostatic
secretory protein, carbonic anhydrase II (128c, 135, 248,
263, 307). Long-term treatment of rodents with estrogens
and androgens (or aromatizable androgens) leads to the
development of adenocarcinomas in distinct prostatic
sites (253, 196). In organ cultures of rat prostates, E2
treatment increases the relative amount of epithelium,
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epididymal sperm, express aromatase (50, 134 –136). This
probably explains the high concentration of E2 in the
testis (135). Both aromatase knock-out (ArKO), and ER␣
knock-out (ERKO) mice show age-related impairment in
testicular function. ArKO mice are initially fertile, but
with advancing age develop dysmorphic seminiferous tubules, spermatogenic arrest and Leydig cell hyperplasia,
and consequently reduced fertility (295). Because there
are no decreases in circulating gonadotropin or androgen
concentrations in ArKO mice, it appears that local E2
production is critical for the maintenance of normal testicular function. In contrast, in ERKO mice, testicular
dysfunction appears to develop in an indirect manner, due
to disturbances in the reabsorption of luminal fluid in the
epididymis. This leads to accumulation of fluid in the
recurrent ducts, dilatation of rete testis and seminiferous
tubules (89, 135), and pressure-related degeneration of
seminiferous tubules. The overall result is disruption of
spermatogenesis with age. The obvious differences between the testicular phenotypes of ArKO and ERKO mice
indicate that ER␣ is not solely responsible for mediating
E2 effects in testis, although it plays a critical role in
regulation of excurrent duct function. Aromatase and
ER␤ are colocalized in the same cells in the testis, suggesting that ER␤, rather than ER␣, could mediate the
actions of locally produced E2. However, Couse and
Korach (77) report that male mice lacking functional ER␤
preserve normal fertility and do not develop the structural
abnormalities typically seen in ERKO mouse testis. Further studies with BERKO mice are warranted to investigate whether there are more subtle changes in testicular
structure and function. In addition, studies with ER␣/ER␤
double knock-out mice (DERKO) (76) will aid in understanding the specific roles of the two ER subtypes in
regulation of testicular development and function.
The potential role of estrogens in regulation of Leydig
cell development and function has recently been reviewed (1). In fetal rats, Leydig cells express ER␣ and
ER␤, whereas in adult rodents and men, only ER␤ has
been detected in Leydig cells (299, 310, 374). Aromatase is
also expressed in Leydig cells in several animal species
including humans (for review, see Ref. 50). During development, E2 inhibits development of Leydig cells from
precursor cells, whereas in adults, E2 can block androgen
production and Leydig cell regeneration (1). The Leydig
cell hyperplasia seen in ArKO mice is consistent with
these findings. It is not yet known whether there are any
Leydig cell-related abnormalities in ERKO, BERKO, or
DERKO mice, and the specific roles of ER subtypes in
Leydig cells remain to be investigated.
Exposure to E2 during development causes multiple
permanent disorders in the structure and function of the
testis and epididymis. In rodents, these include defective
epididymal fluid absorption; decreased expression of a
water channel protein, aquaporin-1, in efferent ducts; di-
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induces changes in epithelial cell shape and organization,
and enhances expression of prostate-specific genes (103,
220, 248). These changes occur in the absence of androgens but may be modulated by simultaneous exposure to
androgens.
C. Estrogens and Prostatic Disease
FIG. 6. Location of ER␤ protein in the human
prostate. In normal prostate (A), the majority of
epithelial cell nuclei express ER␤, whereas the stromal nuclei are negative. In human prostate carcinoma (B), both ER␤-positive and -negative cancer
cells are seen. Positive immunoreaction is indicated
by brown color (arrows). Negative nuclei show only
the counterstain, indicated by the blue color. Immunostaining was performed with a chicken antibody
raised against the full-length human ER␤ protein,
which was modified by insertion into the ligandbinding domain of the 18-amino acid insert found in
rat ER␤ 503. Original magnifications: 100⫻ (top panels) and 400⫻ (bottom panels).
Physiol Rev • VOL
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Developmental exposure to high doses of exogenous
E2 induces multiple persistent structural and functional
abnormalities in the accessory sex glands. These include
reduction in overall gland size; focal epithelial hyperplasia, metaplasia, and dysplasia; altered hormonal sensitivity; altered expression of ERs and AR; alterations in stromal cell growth and function; disturbance of TGF-␤
signaling system; induction of protooncogenes; and inflammatory changes (9, 58, 59, 196, 282, 283, 288, 309,
331). In contrast, exposure to low doses of E2 has been
reported to increase prostate size in adulthood (378). The
effect of subtle changes in intrauterine hormone milieu is
indicated by the stimulation of prostate growth in male
fetuses by intrauterine proximity to female fetuses (354).
Animal experiments suggest that E2 plays a role in the
development of prostatic neoplasia, i.e., benign prostatic
hyperplasia (BPH) and prostate cancer. Excessive E2 exposure leads to enhanced growth of both stromal and
epithelial components and to abnormal cell function (9,
58, 59, 196, 282, 283, 307, 309, 331). In one study, ER␣ but
not ER␤ was found (37) in human prostate cancer and
premalignant prostate lesions (high-grade prostatic intraepithelial neoplasia). Recent results (unpublished results,
Fig. 6), however, indicate that there is widespread expression of ER␤ in the nuclei of epithelial cells in human
prostate cancer. There are always difficulties in interpretation of immunohistochemical data, and caution must be
used, but the prostate poses a special problem in this
regard. Because of the complexity of the gland, sections
from the same prostate gland can display completely
normal morphology, hyperplasia, and cancer, depending
on the region sectioned. It is almost impossible to identify
which part of the organ is represented in an immunohistochemical section. Regional differences in the sections
used in various laboratories might account for some of
the differences reported.
The specific roles of the two ER subtypes in the
development and growth of normal and neoplastic prostate are not known. However, ER knock-out mice have
revealed that lack of functional ERs leads to receptorspecific structural and/or functional alterations in the
prostate. Recently, Couse and Korach (77) reported that
the size of accessory sex glands, prostate, and seminal
vesicles is increased in ERKO mice, and this phenotype
becomes more pronounced when the animals age. We
have also observed that the overall size of accessory sex
glands is increased in ERKO mice. In addition, we have
found morphological changes in the ventral prostate
where the lumina are enlarged and the glandular epithelium flattened (Fig. 7). The exact cause of these changes
has not been defined, but Couse and Korach (77) suggest
that increased size may be due to the slightly elevated
androgen concentrations in ERKO mice.
In contrast, the prostates of BERKO mice frequently
show foci of epithelial hyperplasia and disorganization
(406a) (Fig. 7). DERKO mice share some of the phenotypic characteristics of both ERKO and BERKO mice. The
accessory sex glands are large, but the ventral prostate
MECHANISMS OF ESTROGEN ACTION
1551
shows foci of epithelial disorganization, whereas some
acini are large and lined with flattened epithelium (Fig. 7).
Although the role of ER␤ in the prostate is not known,
development of prostate hyperplasia in BERKO mice suggests a role in regulation of prostate growth. ER␤ and the
androgen receptor (AR) are widely expressed in prostate
epithelium (181) and are colocalized in the same cells.
Because castration causes downregulation ER␤ expression (284), androgens may have a role in regulation of
ER␤ and, perhaps, ER␤ in turn may modulate the growth
stimulating effects of AR.
D. Expression of ERs and Estrogen Action
in Lower Urinary Tract
Urinary bladder function in rodents shows marked
gender-related differences (68, 207) and changes dramatically with sexual maturity (68). Furthermore, neonatal
estrogen exposure induces permanent functional abnormalities in the lower urinary tract of male and female
mice (207). In female rats and rabbits, the function of the
urinary bladder and urethra in vitro is affected by E2 (26,
40, 137, 207, 320). However, the mechanisms of E2 action,
and the role of ERs, are not yet understood. Many of the
rapid E2-induced changes in the function of lower urinary
tract have been postulated to be due to non-receptormediated actions. However, ER, in particular ER␤, is
present in the lower urinary tract, indicating that ERmediated actions are possible as well. Several studies confirm the presence of ERs in distinct sites of the male lower
urinary tract. In the canine and rabbit prostatic urethra,
both epithelium and stroma display specific ER␣ staining
Physiol Rev • VOL
(137, 314). In the mouse, there are ER␣-positive cells in
the stroma of the bladder base, bladder neck, and posterior periurethral region (207). No ER-positive cells were
observed in human bladder biopsy material (36a, 37).
Twenty-seven years ago it was found that the male
baboon bladder could accumulate radiolabeled E2 (382),
but no ER␣ could be detected. More recently, it has been
clearly shown that male rat urinary bladder and rat and
monkey prostatic urethra express ER␤ (184, 269, 310).
ER␤-positive cells have been detected in urothelium, detrusor muscle, and rhabdosphincter, while fibroblasts are
mainly ER␤ negative but may express ER␣. Enlarged
bladder, thickened bladder wall, and occasionally bladder
stones have been detected in neonatally estrogenized
mice, suggesting the presence of E2-related infravesical
obstruction. In accordance with this, neonatally estrogenized mice had lower voided urine volumes, higher voiding frequencies, and decreased ratio of the urinary flow
rate to the bladder pressure (204). In male rats, neonatal
E2 treatment causes symptoms typical of rhabdosphincter dyssynergia, i.e., inappropriate contraction or failure
of relaxation of the urethral smooth and/or striated muscle during detrusor contraction (339). This is indicated by
altered electromyographic activity and impaired urinary
flow rates. Neonatally estrogenized animals also developed changes in the bladder structure typical of obstruction.
XII. ESTROGEN AND THE MAMMARY GLAND
The female mammary gland undergoes a surge of cell
division during puberty, and throughout adult life there is
cyclical proliferation and involution during estrous cycles
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FIG. 7. Morphology of the ventral prostate in ERKO, BERKO, and DERKO mice. In the wild-type mouse (A), ventral
prostate acinae are lined by single layer columnar or cuboidal epithelium, and the lumina are wide. In ERKO mice (B),
the lumina are enlarged, and the epithelium is flat. In BERKO mice (C), the epithelium is folded, multilayered, and
disorganized. In DERKO mice (D), both large acinae with flat epithelium and smaller acinae with multi-layered
epithelium are seen. Original magnifications: 100⫻ (top panels) and 400⫻ (bottom panels).
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NILSSON ET AL.
Physiol Rev • VOL
In the rat mammary gland, both ER␣ and ER␤ are
expressed, but the presence and cellular distribution of
the two receptors are distinct. ER␤ is present in ⬃70% of
epithelial cell nuclei. The percentage of ER␣-positive nuclei varies according to the developmental state of the
mammary gland. It is 30% at puberty and decreases
throughout pregnancy to a low of 5% at day 14 of pregnancy. During lactation there is induction of ER␣ with up
to 70% of the nuclei positive at day 21. Cells coexpressing
ER␣ and ER␤ are rare during pregnancy, a proliferative
phase, but represent up to 60% of the epithelial cells
during lactation, a nonproliferative, E2-insensitive phase
(327, 328). That colocalization of ER␣ and ER␤ is associated with insensitivity to E2 is perhaps not surprising in
view of the existence of ER␤ isoforms that can inhibit
ER␣ activity (257, 306a). One important question that has
arisen since the cloning of ER␤ is whether it would be of
clinical value to measure ER␤, along with ER␣, in breast
cancer. It seems that it will not be sufficient to simply
measure whether or not ER␤ is expressed. It may be
necessary to define which isoforms of ER␤ are present in
cells and whether or not they are colocalized with ER␣.
Depending on the ER␤ isoform, high levels of ER␤ might
mean insensitivity to E2 or inhibition of ER␣ activity if the
receptors are colocalized, or it might simply mean that an
estrogen receptor is present in so-called “estrogen receptor negative cells.”
XIII. ROLE OF ESTROGEN RECEPTORS
IN BONE
Estrogens and androgens play important roles in
bone metabolism and homeostasis. During adolescence,
they are involved in modeling of bone. They initiate pubertal growth and later limit longitudinal bone growth by
inducing closure of the epiphysial growth plate. In adults,
sex steroids appear to influence the remodeling of bone.
E2, in particular, is crucial for maintenance of bone mass
in females (234) as is evident from the rapid loss of
trabecular bone and development of osteoporosis that
occurs after ovariectomy or at menopause (364, 366).
Several factors, known to be important in regulating
differentiation and function of osteoblasts and osteoclasts, are regulated by E2. In osteoblasts, E2 stimulates
synthesis and secretion of the anabolic growth factor
IGF-I and inhibits that of the cytokines, IL-1, tumor necrosis factor (TNF), and IL-6 (298) that are involved in
bone resorption. (96). E2 also stimulates synthesis and
secretion of osteoprotegrin (OPG), a protein with a critical role in inhibition of the function of osteoclasts (138,
154). OPG, together with osteoclast differentiation factor
(ODF) and receptor activator of NF␬B (RANK), all members of the TNF-␣ or TNF-␤ receptor superfamilies, form
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(302). E2 is obligatory for normal development as well as
for induction and progression of mammary carcinoma.
The role of ER in this process remains unclear (143).
During pubertal growth and during the estrous cycle the
majority of proliferating cells both in terminal end buds
and ducts are ER␣ negative (69, 70, 404). Induction of the
progesterone receptor (PR) by E2 does occur in ER␣containing cells, and this induction occurs at much lower
plasma levels of E2 than are required for epithelial cell
proliferation (70). These observations have led to the
concept (391) of two distinct types of responses to E2 in
the breast: 1) an indirect action in the mammary epithelium which occurs via ER-containing stromal cells and
2) a direct effect on ER␣-containing cells that occurs at
low E2 concentrations and results in induction of PR and
differentiation of the epithelium. The stroma, upon E2
stimulation, produces growth factors that cause replication of epithelial cells. From studies involving ERKO mice
it is clear that ER␤, in the absence of ER␣, cannot mediate
E2-dependent growth and development of the mammary
gland (75, 77). In addition, with the use of reconstitution
experiments with ERKO mouse breasts (81) it has been
shown that the presence of ER␣ in breast stroma, but not
in the epithelium, is sufficient for E2-dependent ductal
growth.
Surprisingly, when ER␤ was localized in the mammary gland, it was discovered that very few of the proliferating cells express ER␤. Approximately 60% of proliferating cells contained neither ER␣ nor ER␤ (306). This
observation raises the question, Why do ER␣-containing
cells not divide? The answer to this question is not
known, but if growth of epithelial cells is due to stimulation by growth factors, it appears that ER␣-containing
cells do not have the capacity to respond to growth factor
stimulation. This then raises another question, Why do
ER␣-containing breast cancer cells divide in response to
E2? There is no clear answer to this question either, but
there is evidence that one of the changes occurring in
breast cancer is induction of growth factor receptors (97,
210). It is possible that ER␣ suppresses expression of
certain growth factor receptors in normal mammary epithelium and that upon E2 withdrawal, as occurs during
menopause, there is expression of growth factor receptors on ER-positive cells. Once this has occurred, ER can
be activated by growth factor-stimulated tyrosine kinases
(90, 114, 219, 273) and the normal regulation of cell
growth is lost. Why then do antiestrogens offer temporary
help in breast cancer? It could be speculated that blocking
of ER with tamoxifen inhibits growth factor production in
stromal cells, and this temporarily limits the growth of
epithelial cells. However, blocking of ERs in this system
has the unwanted effect of increasing growth factor receptors and eventually the epithelial cells become more
sensitive to growth factors.
MECHANISMS OF ESTROGEN ACTION
Physiol Rev • VOL
(312). There is a decrease in serum levels of IGF-I and
osteocalcin in male ERKOs, suggesting involvement of the
growth hormone-IGF-I axis in the bone phenotype (377).
In contrast to the ERKO phenotype, adult (3-mo-old)
female BERKOs have an increased limb length and increased (30%) cortical bone mineral content. Trabecular
bone is normal (377, 395). No abnormalities have been
found in the bones of adult male BERKO mice, and the
bone phenotype in DERKO mice is similar to that ERKO
mice (unpublished observations).
These findings suggest that ER␣ mediates the
growth-promoting effects of E2 but is not involved in
maintenance of trabecular bone. The major role of ER␤
during pubertal growth is to terminate the growth spurt in
females, limiting longitudinal and radial bone growth. A
normally functioning ER␤ may, therefore, be responsible
for the shorter bones and lower peak bone mass normally
seen in female rodents. This is also possibly true in women.
In the human population, one subject (a male) has
been reported lacking functional ER␣ protein (336) and
two have been described with total lack of E2 due to
mutations in the aromatase gene (49, 241). In contrast to
the male mice, these men all showed continued linear
growth through adulthood due to unclosed epiphyses.
They had low bone age and severe osteoporosis associated with decreased trabecular bone density. Aromatasedeficient males responded to E2 treatment by growth
plate closure and increased bone mineral density. Further
studies are clearly needed to clarify the cellular and molecular mechanisms behind the phenotypic alterations
observed in the ER knock-out animals and, most interestingly, why the bone phenotypes in these mouse models
differ from those of men with similar defects.
XIV. EVOLUTION OF NUCLEAR RECEPTORS
Nuclear receptors constitute an ancient protein family, found in most or all metazoan animals. Members of
the ERR orphan receptor family probably represent the
earliest precursors of the ERs, since they are found in
very primitive animals such as corals.
A strikingly similar set of steroid receptors is present
in most vertebrates, ranging from fish to mammals. What
complicates the picture is that some species, particularly
fish and some amphibians, for example, Xenopus, have
undergone tetraploidization at some relatively recent time
point during evolution.
A. ERs in Fish
All fish studied so far have an ER␤ homolog (60, 352,
355). In addition to ER␤, they all have another ER, but it
is not clear if this receptor is a true ER␣ homolog or repre-
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a network that regulates osteoclastic differentiation and
function (5, 154, 157, 329). RANK, a membrane-bound
TNF receptor, is expressed on osteoclast precursors. It
interacts with ODF present on the surface of osteoblast/
stroma cells, and this interaction permits differentiation
and subsequent activation of osteoclasts. OPG, secreted
from osteoblasts, is an endogenous, soluble decoy receptor for ODF. It competes with RANK for the binding of
ODF and thus inhibits osteoclast formation. The physiological importance of these factors has been demonstrated in transgenic mice. Mice overexpressing OPG lack
osteoclasts and develop osteopetrosis. In contrast, mice
in which the OPG gene is inactivated have severe osteoporosis (45, 329).
Suppression of osteoclastic bone resorption and
stimulation of osteoblastic bone formation form the basis
for the bone-preserving effects of E2. These diverse actions of E2 on bone raise the question whether the two
ERs have distinct functions and whether cellular localization of the two receptors differs in bone. In humans and
rodents, both ER␣ and ER␤ have been detected in osteoblast-like cell lines (6, 17, 35, 94, 174, 261), in osteoblasts
and osteocytes in bone tissue (43, 144, 147, 186, 261, 262,
394), and in chondrocytes in the epiphysial growth plates
(167, 186, 252, 376). The presence of ERs in mature osteoclasts is more controversial (147, 252, 262, 270).
At the mRNA level, ER␣ is ⬃10-fold more abundant
than ER␤ in trabecular bone, but neither ER mRNA has
been detected in cortical bone (209). In long bones of
immature male and female rats ER␣ levels are higher than
those of ER␤, and ER␤ mRNA is expressed in trabecular
osteoblasts (348). Current information suggests that both
ER␣ and ER␤ have overlapping distribution in cells of the
osteoblastic and chondrocytic lineages. Effects of E2 on
osteoclasts appear to be indirect, through elaboration of
regulatory factors such as OPG by osteoblasts or by bone
marrow stromal cells.
In immature rodents, gonadectomy leads to attenuation of the sexual dimorphism normally seen in bone (364,
365). Limb length in males is decreased, while in females
it is increased. In adult rodents, gonadectomy leads to
increased bone turnover as well as decreased trabecular
bone volume and cortical thickness (348, 163, 372), all of
which can be reversed by either estrogen or androgen
replacement (163, 348, 366, 372). Neither ERKO nor
BERKO mice show any significant alterations in bone
phenotype before the onset of puberty (377, 394). However, in adult mice, both receptors appear to be necessary
for normal bone development. Loss of ER␣ is associated
with decreased longitudinal and radial limb growth and
cortical osteopenia as a result of decreased radial growth
in both sexes (312, 377). Female ERKOs have elevated
levels of serum E2, and ovariectomy of both ERKO and
wild-type female mice results in loss of trabecular bone
1553
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NILSSON ET AL.
XV. CONCLUDING REMARKS
Understanding of E2 physiology and mechanisms of
action has undergone a paradigm shift during recent years
following the discovery of the second estrogen receptor
ER␤. Even though much remains to be done for a full
understanding of the role of this new receptor, it is safe to
conclude that ER␤ is of importance for E2 signaling. For
instance, the function of the ovaries is severely impaired
in the absence of ER␤, and other aspects of reproductive
physiology appear to be affected. It can be anticipated
that continued analysis of BERKO mice will reveal many
other interesting deficiencies and malfunctions. One important characteristic of ER␤ seems to be its capacity to
modulate the biological activity of ER␣ (388) in the sense
that ER␣ is counteracted by ER␤ as if ER␣/ER␤ would
represent an example of the yin-yang principle. Of particular interest is that this quenching effect of ER␤ on ER␣
function seems to be exerted particularly efficiently by
some of the many isoforms of ER␤ that exist, rather than
by the originally discovered receptor, now designated
ER␤1. There is accumulating evidence that, in ER␤
knock-out mice, those phenotypic features that are related to unrestrained ER␣ activity (388) are exaggerated
in mice whose diet contains high levels of phytoestrogens.
This could be one of the reasons for the differences in the
severity of BERKO phenotype observed in different laboratories. Furthermore, the realization that there are two
ERs with somewhat different tissue distribution has
strongly boostered the interest of the pharmaceutical industry to try to develop tissue-specific E2 agonists and
antagonists, to be used in a multitude of clinical states,
e.g., menopausal symptoms such as osteoporosis, cardiovascular disease, urinary incontinence and recurrent urinary infections, hot flashes and mood swings (substitution therapy), as well as breast cancer (estrogen antagonists) and age-related central nervous system degenerative changes.
FIG. 8. Homologies between the different domains of the mouse ER␤, human
ER␣, and fish ER. Comparison of exon/
intron boundaries in these ERs are
shown.
Physiol Rev • VOL
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sents an additional ER subtype. These “non-ER␤”-ER sequences are much less similar to mammalian ER␣ than
the fish ER␤s are to mammalian ER␤ and are as different
from ER␣ as from ER␤ (Fig. 8). This could be regarded as
supportive evidence for a third ER subtype, an “ER␥.” The
ERR␥ subtype, for example, is much more similar to
ERR␤ than to ERR␣ (141). Support for the notion of a
gene that diverged from a ER␣/ER␤ precursor gene (Fig.
9) comes from analysis of the genomic structure of fish
ER. The exon/intron organization of the fish “non-ER␤”-ER
differs from that of both ER␣ and ER␤, in that the D
domain is divided into two exons (206, 350).
At present, we can only make guesses about the total
number of nuclear receptor genes in various species. One
model that has been presented is the “one-to-four rule.”
According to this model, every invertebrate gene should
have four vertebrate paralogues (258). Exceptions to this
rule would stem from subsequent deletion of parts of the
genome. Attempts have been made to fit the known nuclear receptor genes into such a scheme (258), and although the available data are probably incomplete, most
nuclear receptor genes seem to appear in groups of three
rather than of four homologous genes. The exceptions to
this are in fact the steroid receptors and their relatives.
Thus one unknown and probably extinct precursor has
evolved into four related steroid receptors: the glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Furthermore, there are four known members of
the ERR family, three expressed genes (117) and one
pseudo gene (333), but only one identified Drosophila
ERR. To date, there are two known mammalian subtypes
of ER. According to the one-to-four rule, the possibility
thus exists that more ERs remain to be discovered.
Whether or not a functional ER␥ exists in mammals is an
issue that must be resolved soon, since the biological
functions of E2 cannot be understood unless all the participants in the system are known. Analysis of E2 responsiveness in DERKO mice, which have neither functional
ER␣ nor ER␤, will be invaluable in resolving this issue.
MECHANISMS OF ESTROGEN ACTION
1555
This review was made possible by support from a grant
from the Swedish Cancer Fund.
Address for reprint requests and other correspondence:
J.-Å. Gustafsson, Dept. of Medical Nutrition, NOVUM, Huddinge
University Hospital, S141 85 Huddinge, Sweden (E-mail: jagu
@smtp.biosci.ki.se).
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