Send Orders of Reprints at reprints@benthamscience.net
392
Current Molecular Pharmacology, 2012, 5, 392-400
Estrogen Receptor Expression and its Relevant Signaling Pathway in
Prostate Cancer: A Target of Therapy
Yasuhiro Nakamura*, Keely M McNamara and Hironobu Sasano
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
Abstract: Estrogens have been recently postulated as potential agents in the development and progression of prostate
cancer. Previous studies have demonstrated presence of both variants of estrogen receptor (ER); ER alpha (ER) and ER
beta (ER) in differing proportions between normal prostate and prostate cancer. It has been previously suggested that
estrogens may either accelerate or inhibit growth of prostate cancer cell growth, depending on ER status. In particular,
ER is considered to have a growth inhibitory role in prostate tissue. ER is significantly expressed in human prostate
cancer cells, and hence it is considered a key factor for anti-cancer therapy. Therefore, various types of ER ligands have
been investigated to clarify the mechanism of ER-mediated pathway of inhibitory effects on prostate cancer cells.
Herein, we review recent examinations of ERs in prostate cancer, and the significance of ER mediated signaling
pathways, with a focus on ER, as prospective therapeutic targets in prostate cancer.
Keywords: Estrogen receptor alpha(ER), estrogen receptor beta (ER), GRP30, prostate cancer, steroid metabolism.
INTRODUCTION
It has been previously suggested that in addition to the
well characterized actions of androgens, estrogens may
either accelerate or inhibit growth of prostate cancer cell
growth, depending on ER status and ER subtype. Due to this
it becomes very important to clarify the regulatory system(s),
the signaling pathway(s) and ligands of ER in prostate
cancer. In the present article, we focus on the previous and
recent accumulating references regarding the expression and
function of classical estrogen receptors (ER), mainly ER beta
(ER), as well as a new plasma membrane receptor and
discuss the possibility as prospective therapeutic targets in
prostate cancer.
ESTROGEN RECEPTOR: DISTRIBUTION, FUNCTION
AND RESPONSIVE GENES
There are two classical ERs; ER and ER. These proteins
originate from two different genes (6q24-q27 and 14q22-24
respectively) [1, 2]. The two estrogen receptors have a
different distribution pattern among different tissues in the
body, between genders and between species [3-6]. ER and share a large degree of homology in the DNA binding domain
(96% homology) but differ significantly in the N terminus
(20% homology), hinge (30% homology) and ligand binding
domains (53% homology) [7]. In addition to structural
difference between wild type ER and , recent studies have
found alternate isotypes of each receptor [7-9, 10-15] that have
biological relevance to disease states [8, 16]. These alternate
isotypes are achieved by different mechanistic means between
ER and ER. While the principal alternate variants of ER
appear to be formed by exon skipping [17] and hence not
*Address correspondence to this author at the Department of Pathology,
Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai,
980- 8575 JAPAN; Tel: +81-22-717-8050; Fax: +81-22-717-8051; E-mail:
yasu-naka@patholo2.med.tohoku.ac.jp
1874-4702/12 $58.00+.00
concentrated to any domain, the most common ER variants,
are formed by variation within the sequence of exon 8 [13, 18]
(encoding the N terminus and ligand binding domain region).
Estrogen receptors are suggested to have both genomic
and non genomic mechanisms of action. In the genomic
signaling pathway, ER agonists bind causing a structural
change in the receptor that leads to loss of repressor protein,
gain of co-activators and ultimately the receptors, translocation into the nucleus [19]. Antagonist binding leads to an
alternate confirmation change resulting in further recruitment
of receptor co-repressors and inhibition of signaling despite
its inability to translocate and bind DNA [19]. Following
nuclear translocation receptor agonists cause estrogen
receptor to bind estrogen response elements in order to exert
effects on genomic transcription [20]. The estrogen receptor
can do this either as a homodimer (ERER or ERER) or
a heterodimer (ERER) between the two ER variants
depending on various local conditions [21, 22]. As some
DNA binding sites are permissive of both ER and/or ER
binding where as others are specific to ER variant [23], this
explains one way in which different transcriptional programs
can be enacted by the two receptors. In addition to variation
in receptor binding sites each receptor also differs in the cofactors and co-repressor requirements [24], providing
addition levels of control of genomic transcription. Aside
from genomic pathways there are also suggested nongenomic pathways of estrogen action. While the extent and
the role of these have continued to be controversial there is
some evidence suggesting that the genomic and non-genomic
pathways may be synergistic [25].
Estrogen responsive genes are many and vary between
tissues. Some transcriptional programs are inducible by
estrogen receptor while others are specific to receptor type
[26]. In general, in hormone dependent tissues such as the
prostate and breast, ER is thought to enact an antiproliferative gene expression program and ER enacts a proproliferative expression program [27] while the heterodimers
© 2012 Bentham Science Publishers
Estrogen Receptor Expression and its Relevant Signaling Pathway in Prostate Cancer
of the two receptors are suggested to have anti-proliferative
actions [28]. Specifically in the prostate it has been demonstrated that ER promotes abnormal differentiation [29-31]
and in contrast ER action has been shown to act against
proliferation via its regulation of epithelial differentiation
[32-36]. In the prostate ER mediated growth inhibition
mechanisms have been recently elucidated to be an AR
independent via TNF, mediator of apoptosis in the epithelia
and to a lesser extent in stromal cells [37], illustrating the
fundamental importance of ER, independent of other
nuclear receptors, to the regulation of growth in the prostate.
ER EXPRESSION IN PROSTATE CANCER TISSUES
AND CANCER CELL LINES
Since the suggestion of estrogens as having a role in
prostate cancer progression there have been a multitude of
recent studies on ER expression in prostate cancer tissues
across a number of species and human prostate cancer cell
lines [38]. While the variation in detection methods used
(RNA vs IHC vs western blotting) does not always allow
direct comparisons and, particularly with studies involving
ER the availability of a robust ER antibody has been
problematic [39], a growing body of evidence detailed
below, examining ER expression in normal and diseased
prostate exists.
In normal adult and fetal human prostate the predominate receptor expressed is ER [40-42]. In the adult its
strongest expression is in the basal epithelial cells and the
weakest in the luminal epithelial cells with some expression
Current Molecular Pharmacology, 2012, Vol. 5, No. 3
393
in the stroma [40, 43]. ER is also expressed with strongest
reactivity in the stromal cells with little reactivity observed
in the epithelial layer of the prostate [43] and is variable
between individuals well as between nationalities [44]. Both
receptors have been shown to vary between the different
zones of the human prostate [45].
In prostate pathology, ER and ER have been shown to
be present in stromal and epithelial layers of the prostate [43,
45-48] (Fig. 1). In normal prostate and early disease the ratio
of ER/ER in the epithelial layer has been stressed as an
important predictor of the aggressiveness of epithelial
carcinomas [49, 50], with higher levels of ER expression
being beneficial, although this association is not as clear in
later stage disease. In PIN lesions ER expression is thought
to be decreased while ER expression increased [46] in the
epithelial layer [45, 51]. In contrast to findings in PIN lesions,
the patterns reported for estrogen receptor expression in
prostate cancer grade are less consistent. Studies have
suggested that ER expression may be increased in PCa
tissues [46, 52, 53], in a manner akin to what is seen in PIN
although this is not consistent in all papers. Likewise there has
been variability reported in ER immunoreactivity including;
decreased ER immunoreactivity with increasing grade of
prostate cancer [43, 47, 48, 51-57], no significant change by
grade [45, 58] and increase in ER [59-61] in cancer (mRNA
expression). A possible explanation for the variance in
reported ER expression with cancer progression is the
differing specificity of ER antibodies used, and potential
differential expression of ER subtypes. Recent studies have
suggested that the expression pattern of subtypes 2 and 5
A
C
B
D
Fig. (1). Staining for ER (A,C) and ER (B,D)expression in normal (A,B) and cancerous (C,D) prostate. In the above photomicrographs the
predominance of ER in normal and diseased prostate can be observed.
394 Current Molecular Pharmacology, 2012, Vol. 5, No. 3
Nakamura et al.
varies in regard to cell layer specificity and sub-cellular
localization [16]. In addition expression of types 2 and 5 is
associated with worse survival in prostate cancer specimens
[16, 62]. As different ER antibodies are directed against
different regions of ER protein [63, 64] it is possible that
patterns of specific subtypes may have been variably detected,
hence explaining some of the variations observed in
expression pattern with cancer progression. Further studies are
needed to determine the exact expression patterns of ER, and
specifically ER and its associated subtypes, with advancing
grades of prostate cancer.
lines. While the contradictory reports regarding ER may be
explained by differences in antibodies and their ability to
detect ER variants, further work is needed to fully
characterize the ER balance in the most commonly used
prostate cancer cell lines and reconcile the contradictions in
the current literature.
In addition to primary prostate cancer, studies have also
examined the expression of ER in hormone refractory and
metastatic disease. In the former, both ER and have been
reported to be expressed [52, 57, 65, 61] and in the latter
ER has been reported to be expressed despite loss of ER
expression in progression of the original prostate cancer [66,
67]. This report suggests that ER may be a possible target
even in advanced disease, although its underlying biological
role is, at this point, unknown.
It is known that the action of ERs, especially ER, is
different depending on the ligand. While there are many
different proposed ligands of the estrogen receptor, in this
paper we are going to limit discussion to the effects of the
two most widely studied naturally occurring ligands, E2 and
5-androstane-3,17-diol (3-adiol), in addition to a
variety of synthetic compounds.
The effects of various prostate cancer treatments on
hormone receptor expression have also been examined. Following hormone deprivation and the subsequent emergence of
hormone refractory disease ER is suggested to be increased
relative to ER levels [57, 65, 52] implying that in hormone
refractory disease a contributing factor may be loss of ER
mediated suppression of proliferation, in addition to the well
characterized changes in androgen dependent signaling
suggesting a potential for targeting estrogen receptors
following failure of androgen dependent therapy. Nonendocrine based therapy directed at primary cancers may
also inadvertently act on the androgen-estrogen axis. Studies
examining hormone receptor levels following radiation
treatment showed increased levels of all steroid receptors
including ER however these increases were at different
rates with AR being the least affected. This is interesting as
it suggests that radiation exposure may affect the balance of
androgen and estrogen signaling in the prostate [68], thus
suggesting even in treatments that do not specifically target
the hormone receptors there may be residual effects on
hormonal pathways through alteration of receptor levels.
In addition to prostate cancer tissues a variety of prostate
cancer cell lines have also been examined in regards to ER
and ER expression. The most commonly examined cell lines
are the PC3, LNCaP and DU145 [58, 61, 69-75] with other
prostate cancer cell lines (i.e. JCA-1, ND1, DUPro, PC3M and
22Rv1) being examined in a limited number of studies [58, 61,
70, 71]. In general, all prostate cancer cell lines have been
demonstrated to express ER [58, 61, 69-75] although some
studies suggest that ER expression is reduced through
methylation silencing [71] suggesting one way in which
expression could be modulated in prostate cancer tissues. In
contrast to ER, expression levels of ER have not been
examined in too much depth and when examined are more
contradictory. The majority of work looking at the expression
of ER in prostate cancer cell lines has focused on the LNCaP
and PC3 lines. Some [61, 71] but not all reports [58, 69, 70,
72-75] have reported detectable levels of ER expression
although this is a limited panel of prostate cancer cell lines
when compared to studies examining ER expression in cell
LIGANDS
OF
ESTROGEN
RECEPTOR
IN
PROSTATE CANCER AND THEIR PATHWAYS FOR
ACTION
There are two main naturally occurring estrogenic ligands
that have been discussed in the context of the prostate.
Estradiol (E2) is the steroid with the highest affinity for ER
in vivo. While actions of estradiol in the prostate were
historically a paradox due to the very low levels of serum
estrogen in males, the demonstration of the importance of
intracrinology in hormone dependent tissues and specifically
the demonstration of in situ production of estrogen in prostate
cancer tissues (Fig. 2), [76, 77] has lead to a burgeoning
research field surrounding intracrine estrogen metabolism in
the prostate. Research within this field, has suggested an
alternate pathway of intracrine production of estrogenic
ligand compounds in the prostate. 3b-adiol is known as a
putative natural ERb-ligand, albeit with a lower affinity for
ER than E2. 3b-adiol is a metabolite of DHT, produced by
17b-hydroxysteroid
dehydrogenases and
is further
metabolized to triols by CYP7B1 [78, 79]. The local level of
3b-adiol is reported to be much higher than that of E2 in the
prostate [33, 79] and due to this it has been proposed that
3diol may be the more physiologically relevant ligand of ERs
in prostate tissue. Based on the above findings, while the exact
estrogenic ligand is unclear it is reasonably postulated that
locally produced estrogens play a role in prostate cancer cell
biology via ERb.
One very interesting aspect of the E2 vs 3diol controversy is the suggestion that the two different ligands may
mediate different biological outcomes. This suggestion comes
from studies across a number of cell lines. E2 administration
has been shown to mediate effects associated with
proliferation in a number of cell lines including the induction
of PSA mRNA in response to E2-ER interaction in LNCaP
cells [80] and the induction of cell proliferation mediated
through E2 induced proteasome-dependent degradation of
KLF5 in DU145 cells [81]. In contrast to the effects of E2 in
prostate cancer cell lines 3b-adiol has been demonstrated to
inhibit the proliferation of DU-145 and PC-3 cells [82, 83]
suggesting a ligand specific effect of estrogen actions. When
compared to expected observations based on clinical samples
the effects of 3diol seem to match the lower proliferation and
better outcome observed in ER+ prostate cancer patients.
However further studies are needed to fully understand if the
effects of E2 and 3diol administration are a faithful model of
cell line effects in prostate cancer.
Estrogen Receptor Expression and its Relevant Signaling Pathway in Prostate Cancer
Vessel
395
Prostate cancer tissue
Aromatase
Androstendione
(inactive)
E1S
(inactive)
Current Molecular Pharmacology, 2012, Vol. 5, No. 3
17β-HSD type 1
E1
E2
(active)
STS
ER β
Fig. (2). The postulated scheme representing local production of estrogens in human prostate cancer tissue. High concentration of circulating
inactive steroids, androstenedione, and estrone-sulfate (E1S), are major precursor substrates of local estrogen production in the tissue.
Aromatase catalyzes androstenedione into estrone (E1), and Steroid sulfatase (STS) hydrolyzes estrone-sulfate (E1S) to E1. E1 is
subsequently converted to potent estradiol (E2) by 17 hydroxysteroid dehydrogenase type 1 (17-HSD-1), and acts on target cells via ER in
prostate cancer cells. These three enzymes are expressed in human cancer cells. This figure was referred to in previous reports [76, 77].
Finally, the effects of a number of synthetic agonists and
antagonists, with different affinities for ER and , have
been examined across various prostate cancer cell lines. In
many cases these reagents offer an excellent opportunity to
dissect ER action in the prostate due to the targeted nature of
these agents. Two of these agents are non ER type specific
(ICI 182,720, raloxifine) and one has a very high degree of
specificity to ER (8-VE2). ICI182,780 (ICI), an inhibitor
of ER, has been demonstrated to activate ER resulting in
proliferation of DU145 cells [84]. In contradiction to the ICI
results Kim et al. demonstrated that raloxifene, a mixed
estrogen agonist/antagonist, promotes activation of caspases
8 and 9 in PC3 and DU145 cells and induces their apoptosis
[70] a finding which is possible explained by the preference
of raloxifine for binding to ER [85] compared to the non
specific antagonism of ICI. The final synthetic agent, and
some of the strongest cell study based evidence for ER as a
suppressor of cellular proliferation, is a selective ER
agonist (8-VE2) reported in McPherson et al [37]. In
prostate cancer cells, administration of 8-VE2 activates
apoptosis via TNF [37]. While the results from synthetic
ligands are mixed it would appear that specific activation of
ER results in the activation of apoptosis through various
cellular pathways.
ligands of ER have been those using E2. These studies have
shown that E2 binding causes ER to bind at the ERE, but
inhibits its activity at AP1 sites [78]. In contrast to endogenous
E2 the synthetic ligand, ICI182,780 (ICI), an inhibitor of ER,
has been demonstrated to activate ERb by involving NFkB
complex resulting in proliferation [84]. At the moment there is
insufficient data to correlate any one or combination of E2
binding sites with proliferative or suppressive actions of ER
however this remains an exciting future prospect.
Adding to the complexity in examining the interaction of
ER ligands and receptor, ERb has several binding motifs
including estrogen responsive element (ERE), AP1 and NFB.
As there may be ligand specific actions of ER one possible
mechanism that it could act through is causing the receptors to
undergo a conformational change that gives specificity to one
or more ER binding motifs while restricting access to others.
At the moment the study of the correlation between ligand and
binding motif is in its infancy however initial results suggest
there may be some significance in this hypothesis. To the best
of our knowledge the only studies concerning endogenous
REGULATION OF ER IN PROSTATE CANCER
CELLS
Finally, non genomic pathways of ER signaling have
also proved to be relevant in a prostate cancer setting,
although to the best of our knowledge E2 is the only ligand
investigated in this setting. E2 actions on ER-mediated nongenomic pathway have also been demonstrated as to be
relevant as Pandini et al. found that E2 markedly upregulates insulin-like growth factor -I receptor (IGF-IR)
mRNA and protein expression in both LNCaP and PC-3
cells in a non genomic manner and this increases mitogenic
and motogenic activities of cancer cells [86]. While the
investigations of ER-E2 interaction are still in their infancy,
and the exact relevant balance between genomic and non
genomic actions is unclear this initial finding suggests this
may be an avenue for further investigation.
In addition to varied estrogen receptor ligands, regulatory
factors also play a role in both expression and activity of
ER. While not exhaustive we will briefly discuss some of
the ER co-regulators that have recently been shown to be
important in the regulation of growth in prostate cancer cell
lines in the hope of illustrating the myriad of cofactors that
may affect ER actions and highlighting an area of further
research.
396 Current Molecular Pharmacology, 2012, Vol. 5, No. 3
Nakamura et al.
Steroid receptor coactivators p300 and CBP, are highly
expressed in advanced prostate cancer, have been shown to
potentiate ER signaling and through this pathway inhibit
cellular migration [87]. Peptide hormones such as human
growth hormone (hGH) can stimulate/modulate insulin-like
growth factor (IGF) and ER gene expressions in the
androgen sensitive lines LNCaP and PC3 [88]. In
addition to stimulating ER expression, co-administration of
IGF-I and E2 stimulates androgen-dependent LNCaP cell
proliferation, suggesting a synergistic effect between growth
factor and estrogen signaling pathways [88]. Finally, recent
studies examining interactions between ER established
markers of tissue hypoxia and adverse outcome (eNOS and
HIF) have suggested that ER acts in association with these
markers to initiate transcription and that ER expression in
combination with marker predicts for a worse clinical
outcome [89]. While this is a subset, focused on recent
research, of all studies looking at the association between
ER expression and co-regulatory proteins they illustrate the
complexity and plasticity in ER action, depending on its
associations.
ER RESPONSIVE GENES
Many studies have studied the downstream effects of ER
and ER activation in estrogen dependent cancers such as
breast. These studies can use provide useful information when
trying to extrapolate an understanding of the roles of ER and
in prostate cancer. While specific ER responsive genes have
mainly been studied in relation to ER signaling, the vast
majority of investigations into downstream effect of ER have
been achieved by the study of E2 dependent gene expression
profiles. Such gene expression profiles have revealed links, at
least in breast cancer, between ER signaling, cell cycle
regulators [90] and TGF signaling [91]. Of these, the latter is
the most interesting as there is a link to patterns found in
prostate cancer cell line studies. By using microarray analysis,
Chang et al. investigated gene regulatory effects of ER in the
MCF7 breast cancer cell line. In this study of all the genes
modulated by ER, the greatest numbers were associated with
transcriptional factors and signal transduction pathways,
including TGF, semaphorin and SDF1 signaling pathways
[91]. As TGF is normally associated with the suppression of
cell proliferation in breast cancer cell lines the down
regulation of multiple elements of the TGF pathway by ER
signaling [91] is potentially interesting in view of the
interactions between TGF-1 and prostate cancer cell growth.
It is reported that TGF-1 locally produced by prostate cancer
cells can result in suppression of a paracrine dependent ER
mediated inhibition of cell motility [92]. The reciprocal
regulation of ER by TGF in breast cancer may suggest that,
at least in part, the tumor cells motility is controlled by the
balance between these two signaling molecules, although this
requires study of ER regulation of TGF signaling pathways
in prostate cancer cell lines for confirmation. Likewise the
presence of ER E2 inhibition of cell cycle regulators and
other aspect of cell growth and metabolism observed in the
breast should also be tested in prostate cancer cell lines.
GPR30,
A
NOVEL
PROSTATE
ESTROGEN
RECEPTOR CAPABLE OF INHIBITING PROSTATE
CANCER GROWTH?
While studies have focused on the classical ERs, there
are other cellular proteins capable of mediating estrogen
dependent signaling. Recently, an orphan G protein–coupled
receptor (GPR30), capable of E2 binding [93], has been
found at both the plasma membrane and the endoplasmic
Better prognosis
ERK1/2
p21
GRP30
Cjun/cfos
Cox2
TGFβ
Semaphorin
SDF1
ERβ
p300
ERβ
CBP
ERα
ERβ
Hif
Proliferation
ERβ
eNOS
Worse prognosis
Fig. (3). Suggested pathways of ER action in prostate carcinoma cells. A diagrammatic summary of the suggested pathways of estrogen
signaling in prostate cancer cells. The upper half of the section (light gray) illustrates interaction of estrogenic receptors with downstream
pathways that have a beneficial effect on prostate cancer cells, usually through the inhibition of proliferation. The lower section (dark gray)
illustrates the interactions that have an adverse effect on prostate cancer, through a variety of mechanisms.
Estrogen Receptor Expression and its Relevant Signaling Pathway in Prostate Cancer
reticulum [94]. The function of GPR30 in cancer cell
proliferation has been reported to be different among various
types of cancers [93, 95-99, 100, 101], including prostate
cancer. Chan et al. demonstrated that when a non-estrogenic
ligand (G1) bound to GPR30 it induced inhibition of PC-3
cell growth. The mechanism of this GPR30 mediated growth
suppression was through a sustained activation of Erk1/2 and
a c-jun/c-fos-dependent upregulation of p21 [94] leading to
the inhibition of cell growth. While this suggests GPR30 as a
potential inhibitor of prostate cancer growth further studies
are needed to clarify the significance of GPR30 expression
in the prostate, the biological effect of estrogenic compounds
on this receptor and the interaction, if any, between ER and
GPR30 in prostate.
CONCLUSION
In conclusion, ER in prostate cancer is involved in
various signaling pathways, has many levels of regulation
(summarized in Fig. 3). It is postulated that ER may be a
potential target for prostate cancer therapy, although to allow
the development of useful therapeutic agents more work
needs to be done in order to understand the inherent
mechanisms in ER specific regulation of prostate growth.
IGF
=
Insulin Growth factor
IGF-IR
=
Insulin-like growth factor -I receptor
IHC
=
Immunohistochemistry
mRNA
=
Messenger ribonucleic acid
NFB
=
Nuclear factor kappa B
PCa
=
Prostate cancer
PIN
=
Prostate intraepithelial neoplasia
PSA
=
Prostate specific antigen
RNA
=
Ribonucleic acid
SDF1
=
Stromal cell-derived factor 1
TNF
=
Tumor necrosis factor alpha
[1]
[2]
[3]
The authors confirm that this article content has no
conflicts of interest.
[4]
ACKNOWLEDGEMENTS
[5]
ABBREVIATIONS
397
REFERENCES
CONFLICT OF INTEREST
KM is supported by a Japan Society for the Promotion of
Science-Australian Academy of Science postdoctoral
fellowship.
Current Molecular Pharmacology, 2012, Vol. 5, No. 3
[6]
[7]
3adiol
=
5-androstane-3,17-diol
AP-1
=
Transactivating function 1
[8]
CBP
=
cAMP response element-binding protein
binding protein
[9]
CYP7B1 =
Cytochrome P450 71
[10]
DNA
=
Deoxyribonucleic Acid
eNOS
=
Endothelial Nitric Oxide Synthase
E2
=
Estradiol
ER
=
Estrogen receptor
ER
=
Estrogen receptor alpha
ER
=
Estrogen receptor beta
ERE
=
Estrogen responsive element
GPR30
=
Orphan G protein–coupled receptor 30
HIF
=
Hypoxia inducible factor
hGH
=
Human Growth Hormone
ICI
=
ICI 182,720
[11]
[12]
[13]
[14]
Gosden, J.R.; Middleton, P.G.; Rout, D. Localization of the human
oestrogen receptor gene to chromosome 6q24----q27 by in situ
hybridization. Cytogenet. Cell Genet., 1986, 43(3-4), 218-220.
Enmark, E.; Pelto-Huikko, M.; Grandien, K.; Lagercrantz, S.;
Lagercrantz, J.; Fried, G.; Nordenskjold, M.; Gustafsson, J.A.
Human estrogen receptor beta-gene structure, chromosomal
localization, and expression pattern. J. Clin. Endocrinol. Metab.,
1997, 82(12), 4258-4265.
Morani, A.; Warner, M.; Gustafsson, J.A. Biological functions and
clinical implications of oestrogen receptors alfa and beta in
epithelial tissues. J. Intern. Med., 2008, 264(2), 128-142.
Fasco, M.J.; Hurteau, G.J.; Spivack, S.D. Gender-dependent
expression of alpha and beta estrogen receptors in human nontumor
and tumor lung tissue. Mol. Cell. Endocrinol., 2002, 188(1-2), 125140.
Shughrue, P.J.; Lane, M.V.; Scrimo, P.J.; Merchenthaler, I.
Comparative distribution of estrogen receptor-alpha (ER-alpha) and
beta (ER-beta) mRNA in the rat pituitary, gonad, and reproductive
tract. Steroids, 1998, 63(10), 498-504.
Kuiper, G.G.; Carlsson, B.; Grandien, K.; Enmark, E.; Haggblad,
J.; Nilsson, S.; Gustafsson, J.A. Comparison of the ligand binding
specificity and transcript tissue distribution of estrogen receptors
alpha and beta. Endocrinology, 1997, 138(3), 863-870.
Thomas, C.; Gustafsson, J.A. The different roles of ER subtypes in
cancer biology and therapy. Nat. Rev. Cancer, 2011, 11(8), 597608.
Herynk, M.H.; Fuqua, S.A. Estrogen receptor mutations in human
disease. Endocr. Rev., 2004, 25(6), 869-898.
Taylor, S.E.; Martin-Hirsch, P.L.; Martin, F.L. Oestrogen receptor
splice variants in the pathogenesis of disease. Cancer Lett., 288(2),
133-148.
Petersen, D.N.; Tkalcevic, G.T.; Koza-Taylor, P.H.; Turi, T.G.;
Brown, T.A. Identification of estrogen receptor beta2, a functional
variant of estrogen receptor beta expressed in normal rat tissues.
Endocrinology, 1998, 13(3), 1082-1092.
Chaidarun, S.S.; Swearingen, B.; Alexander, J.M. Differential
expression of estrogen receptor-beta (ER beta) in human pituitary
tumors: functional interactions with ER alpha and a tumor-specific
splice variant. J. Clin. Endocrinol. Metab., 1998, 83(9), 3308-3315.
Rosenkranz, K.; Hinney, A.; Ziegler, A.; Hermann, H.; Fichter, M.;
Mayer, H.; Siegfried, W.; Young, J.K.; Remschmidt, H.;
Hebebrand, J. Systematic mutation screening of the estrogen
receptor beta gene in probands of different weight extremes:
identification of several genetic variants. J. Clin. Endocrinol.
Metab., 1998, 83(12), 4524-4527.
Poola, I.; Abraham, J.; Baldwin, K. Identification of ten exon
deleted ERbeta mRNAs in human ovary, breast, uterus and bone
tissues: alternate splicing pattern of estrogen receptor beta mRNA
is distinct from that of estrogen receptor alpha. FEBS Lett., 2002,
516(1-3), 133-138.
Leung, Y.K.; Mak, P.; Hassan, S.; Ho, S.M. Estrogen receptor
(ER)-beta isoforms: a key to understanding ER-beta signaling.
Proc. Natl. Acad. Sci. USA, 2006, 103(35), 13162-13167.
398 Current Molecular Pharmacology, 2012, Vol. 5, No. 3
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
Scobie, G.A.; Macpherson, S.; Millar, M.R.; Groome, N.P.;
Romana, P.G.; Saunders, P.T. Human oestrogen receptors:
differential expression of ER alpha and beta and the identification
of ER beta variants. Steroids, 2002, 67(12), 985-992.
Leung, Y.K.; Lam, H.M.; Wu, S.; Song, D.; Levin, L.; Cheng, L.;
Wu, C.L.; Ho, S.M. Estrogen receptor beta2 and beta5 are
associated with poor prognosis in prostate cancer, and promote
cancer cell migration and invasion. Endocr. Relat. Cancer, 17(3),
675-689.
Poola, I.; Koduri, S.; Chatra, S.; Clarke, R. Identification of twenty
alternatively spliced estrogen receptor alpha mRNAs in breast
cancer cell lines and tumors using splice targeted primer approach.
J. Steroid Biochem. Mol. Biol., 2000, 72 (5), 249-258.
Moore, J.T.; McKee, D.D.; Slentz-Kesler, K.; Moore, L.B.; Jones,
S.A.; Horne, E.L.; Su, J.L.; Kliewer, S.A.; Lehmann, J.M.; Willson,
T.M. Cloning and characterization of human estrogen receptor beta
isoforms. Biochem. Biophys. Res. Commun., 1998, 247(1), 75-78.
Edwards, D.P. The role of coactivators and corepressors in the
biology and mechanism of action of steroid hormone receptors. J.
Mammary Gland Biol. Neoplasia, 2000, 5(3), 307-324.
Dietz, S.C.; Carroll, J.S. Interrogating the genome to understand
oestrogen-receptor-mediated transcription. Expert Rev. Mol. Med.,
2008, 10, e10.
Powell, E.; Wang, Y.; Shapiro, D.J.; Xu, W. Differential
requirements of Hsp90 and DNA for the formation of estrogen
receptor homodimers and heterodimers. J. Biol. Chem., 285(21),
16125-16134.
Paulmurugan, R.; Tamrazi, A.; Massoud, T.F.; Katzenellenbogen,
J.A.; Gambhir, S.S. In vitro and in vivo molecular imaging of
estrogen receptor alpha and beta homo- and heterodimerization:
exploration of new modes of receptor regulation. Mol. Endocrinol.,
25(12), 2029-2040.
Liu, Y.; Gao, H.; Marstrand, T.T.; Strom, A.; Valen, E.; Sandelin,
A.; Gustafsson, J.A.; Dahlman-Wright, K. The genome landscape
of ERalpha- and ERbeta-binding DNA regions. Proc. Natl. Acad.
Sci. USA, 2008, 105(7), 2604-2609.
Gougelet, A.; Bouclier, C.; Marsaud, V.; Maillard, S.; Mueller,
S.O.; Korach, K.S.; Renoir, J.M. Estrogen receptor alpha and beta
subtype expression and transactivation capacity are differentially
affected by receptor-, hsp90- and immunophilin-ligands in human
breast cancer cells. J. Steroid Biochem. Mol. Biol., 2005, 94(1-3),
71-81.
Bjornstrom, L.; Sjoberg, M. Mechanisms of estrogen receptor
signaling: convergence of genomic and nongenomic actions on
target genes. Mol. Endocrinol., 2005, 19(4), 833-842.
Stossi, F.; Barnett, D.H.; Frasor, J.; Komm, B.; Lyttle, C.R.;
Katzenellenbogen, B.S. Transcriptional profiling of estrogenregulated gene expression via estrogen receptor (ER) alpha or
ERbeta in human osteosarcoma cells: distinct and common target
genes for these receptors. Endocrinology, 2004, 145(7), 3473-3486.
Risbridger, G.P.; Davis, I.D.; Birrell, S.N.; Tilley, W.D. Breast and
prostate cancer: more similar than different. Nat. Rev. Cancer,
2010, 10(3), 205-212.
Powell, E.; Shanle, E.; Brinkman, A.; Li, J.; Keles, S.; Wisinski,
K.B.; Huang, W.; Xu, W., Identification of estrogen receptor dimer
selective ligands reveals growth-inhibitory effects on cells that coexpress ERalpha and ERbeta. PLoS One, 2012, 7(2), e30993.
Ricke, W.A.; McPherson, S.J.; Bianco, J.J.; Cunha, G.R.; Wang,
Y.; Risbridger, G.P. Prostatic hormonal carcinogenesis is mediated
by in situ estrogen production and estrogen receptor alpha
signaling. FASEB J., 2008, 22(5), 1512-1520.
Risbridger, G.; Wang, H.; Young, P.; Kurita, T.; Wang, Y.Z.;
Lubahn, D.; Gustafsson, J.A.; Cunha, G. Evidence that epithelial
and mesenchymal estrogen receptor-alpha mediates effects of
estrogen on prostatic epithelium. Dev. Biol., 2001, 229(2), 432-442.
Omoto, Y.; Imamov, O.; Warner, M.; Gustafsson, J.-Å. Estrogen
Receptor Alpha and Imprinting of the Neonatal Mouse Ventral
Prostate by Estrogen Proc. Natl. Acad. Sci. USA, 2005, 105(5),
1484-1489.
Lindberg, M.K.; Moverare, S.; Skrtic, S.; Gao, H.; DahlmanWright, K.; Gustafsson, J.A.; Ohlsson, C. Estrogen receptor (ER)beta reduces ERalpha-regulated gene transcription, supporting a
"ying yang" relationship between ERalpha and ERbeta in mice.
Mol. Endocrinol., 2003, 17(2), 203-208.
Weihua, Z.; Lathe, R.; Warner, M.; Gustafsson, J.A. An endocrine
pathway in the prostate, ERbeta, AR, 5alpha-androstane-
Nakamura et al.
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
3beta,17beta-diol, and CYP7B1, regulates prostate growth. Proc.
Natl. Acad. Sci. USA, 2002, 99(21), 13589-13594.
Weihua, Z.; Makela, S.; Andersson, L.C.; Salmi, S.; Saji, S.;
Webster, J.I.; Jensen, E.V.; Nilsson, S.; Warner, M.; Gustafsson,
J.A. A role for estrogen receptor beta in the regulation of growth of
the ventral prostate. Proc. Natl. Acad. Sci. USA, 2001, 98(11),
6330-6335.
McPherson, S.J.; Ellem, S.J.; Simpson, E.R.; Patchev, V.;
Fritzemeier, K.-H.; Risbridger, G.P. Essential role for estrogen
receptor beta in stromal-epithelial regulation of prostatic
hyperplasia. Endocrinology, 2007, 148(2), 566-574.
Imamov, O.; Morani, A.; Shim, G.-J.; Omoto, Y.; ThulinAndersson, C.; Warner, M.; Gustafsson, J.-Å. Estrogen receptor
beta regulates epithelial cellular differentiation in the mouse ventral
prostate. PNAS, 2004, 101(25), 9375-9380.
McPherson, S.J.; Hussain, S.; Balanathan, P.; Hedwards, S.L.;
Niranjan, B.; Grant, M.; Chandrasiri, U.P.; Toivanen, R.; Wang,
Y.; Taylor, R.A.; Risbridger, G.P. Estrogen receptor-beta activated
apoptosis in benign hyperplasia and cancer of the prostate is
androgen independent and TNFalpha mediated. Proc. Natl. Acad.
Sci. USA, 2010, 107(7), 3123-3128.
Kawashima, H.; Nakatani, T. Involvement of estrogen receptors in
prostatic diseases. Int. J. Urol.,2012, 19(6), 512-522.
Wu, X.; Subramaniam, M.; Negron, V.; Cicek, M.; Reynolds, C.;
Lingle, W.L.; Goetz, M.P.; Ingle, J.N.; Spelsberg, T.C.; Hawse,
J.R. Development, characterization, and applications of a novel
estrogen receptor beta monoclonal antibody. J. Cell. Biochem.,
2012, 113(2), 711-723.
Pelletier, G. Expression of steroidogenic enzymes and sex-steroid
receptors in human prostate. Best Pract. Res. Clin. Endocrinol.
Metab., 2008, 22(2), 223-228.
Shapiro, E.; Huang, H.; Masch, R.J.; McFadden, D.E.; Wilson,
E.L.; Wu, X.R. Immunolocalization of estrogen receptor alpha and
beta in human fetal prostate. J. Urol., 2005, 174(5), 2051-2053.
Adams, J.Y.; Leav, I.; Lau, K.M.; Ho, S.M.; Pflueger, S.M.
Expression of estrogen receptor beta in the fetal, neonatal, and
prepubertal human prostate. Prostate, 2002, 52(1), 69-81.
Leav, I.; Lau, K.M.; Adams, J.Y.; McNeal, J.E.; Taplin, M.E.;
Wang, J.; Singh, H.; Ho, S.M. Comparative studies of the estrogen
receptors beta and alpha and the androgen receptor in normal
human prostate glands, dysplasia, and in primary and metastatic
carcinoma.[see comment]. Am. J. Pathol., 2001, 159(1), 79-92.
Haqq, C.; Li, R.; Khodabakhsh, D.; Frolov, A.; Ginzinger, D.;
Thompson, T.; Wheeler, T.; Carroll, P.; Ayala, G. Ethnic and racial
differences in prostate stromal estrogen receptor alpha. Prostate
2005, 65(2), 101-109.
Fixemer, T.; Remberger, K.; Bonkhoff, H. Differential expression
of the estrogen receptor beta (ERbeta) in human prostate tissue,
premalignant changes, and in primary, metastatic, and recurrent
prostatic adenocarcinoma. Prostate, 2003, 54(2), 79-87.
Bonkhoff, H.; Fixemer, T.; Hunsicker, I.; Remberger, K. Estrogen
receptor expression in prostate cancer and premalignant prostatic
lesions. Am. J. Pathol., 1999, 155(2), 641-647.
Horvath, L.G.; Henshall, S.M.; Lee, C.S.; Head, D.R.; Quinn, D.I.;
Makela, S.; Delprado, W.; Golovsky, D.; Brenner, P.C.; O'Neill,
G.; Kooner, R.; Stricker, P.D.; Grygiel, J.J.; Gustafsson, J.A.;
Sutherland, R.L. Frequent loss of estrogen receptor-beta expression
in prostate cancer. Cancer Res., 2001, 61(14), 5331-5335.
Asgari, M.; Morakabati, A. Estrogen receptor beta expression in
prostate adenocarcinoma. Diagn. Pathol., 2011, 6, 61.
Miro, A.M.; Sastre-Serra, J.; Pons, D.G.; Valle, A.; Roca, P.;
Oliver, J. 17beta-Estradiol regulates oxidative stress in prostate
cancer cell lines according to ERalpha/ERbeta ratio. J. Steroid
Biochem. Mol. Biol., 123(3-5), 133-139.
Ellem, S.J.; Risbridger, G.P. The dual, opposing roles of estrogen
in the prostate. Ann. N. Y. Acad. Sci., 2009, 1155, 174-186.
Gabal, S.M.; Habib, F.M.; Helmy, D.O.; Ibrahim, M.F. Expression
of estrogen receptor-B (ER-B) in bengin and malignant prostatic
epithelial cells and its correlation with the clinico-pathological
features. J. Egypt. Natl. Canc. Inst., 2007, 19(4), 239-248.
Yang, G.S.; Wang, Y.; Wang, P.; Chen, Z.D. Expression of
oestrogen receptor-alpha and oestrogen receptor-beta in prostate
cancer. Chin. Med. J. (Engl), 2007, 120(18), 1611-1615.
Ji, Q.; Liu, P. I.; Elshimali, Y.; Stolz, A., Frequent loss of estrogen
and progesterone receptors in human prostatic tumors determined
Estrogen Receptor Expression and its Relevant Signaling Pathway in Prostate Cancer
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
by quantitative real-time PCR. Mol. Cell. Endocrinol,. 2005, 229(12), 103-110.
Mak, P.; Leav, I.; Pursell, B.; Bae, D.; Yang, X.; Taglienti, C.A.;
Gouvin, L.M.; Sharma, V.M.; Mercurio, A.M. ERbeta impedes
prostate cancer EMT by destabilizing HIF-1alpha and inhibiting
VEGF-mediated snail nuclear localization: implications for
Gleason grading. Cancer Cell, 2010, 17(4), 319-332.
Muthusamy, S.; Andersson, S.; Kim, H.J.; Butler, R.; Waage, L.;
Bergerheim, U.; Gustafsson, J.A. Estrogen receptor beta and
17beta-hydroxysteroid dehydrogenase type 6, a growth regulatory
pathway that is lost in prostate cancer. Proc. Natl. Acad. Sci. USA,
2011, 108(50), 20090-20094.
Pasquali, D.; Staibano, S.; Prezioso, D.; Franco, R.; Esposito, D.;
Notaro, A.; De Rosa, G.; Bellastella, A.; Sinisi, A.A. Estrogen
receptor beta expression in human prostate tissue. Mol. Cell.
Endocrinol., 2001, 178(1-2), 47-50.
Latil, A.; Bieche, I.; Vidaud, D.; Lidereau, R.; Berthon, P.;
Cussenot, O.; Vidaud, M., Evaluation of androgen, estrogen (ER
alpha and ER beta), and progesterone receptor expression in human
prostate cancer by real-time quantitative reverse transcriptionpolymerase chain reaction assays. Cancer Res., 2001, 61(5), 191919126.
Linja, M.J.; Savinainen, K.J.; Tammela, T.L.; Isola, J.J.; Visakorpi,
T. Expression of ERalpha and ERbeta in prostate cancer. Prostate,
2003, 55(3), 180-186.
Walton, T.J.; Li, G.; McCulloch, T.A.; Seth, R.; Powe, D.G.;
Bishop, M.C.; Rees, R.C. Quantitative RT-PCR analysis of
estrogen receptor gene expression in laser microdissected prostate
cancer tissue. Prostate, 2009, 69(8), 810-819.
Torlakovic, E.; Lilleby, W.; Torlakovic, G.; Fossa, S.D.; Chibbar,
R. Prostate carcinoma expression of estrogen receptor-beta as
detected by PPG5/10 antibody has positive association with
primary Gleason grade and Gleason score. Hum. Pathol., 2002,
33(6), 646-651.
Ito, T.; Tachibana, M.; Yamamoto, S.; Nakashima, J.; Murai, M.
Expression of estrogen receptor (ER-alpha and ER-beta) mRNA in
human prostate cancer. Eur. Urol., 2001, 40(5), 557-563.
Fujimura, T.; Takahashi, S.; Urano, T.; Ogawa, S.; Ouchi, Y.;
Kitamura, T.; Muramatsu, M.; Inoue, S. Differential expression of
estrogen receptor beta (ERbeta) and its C-terminal truncated splice
variant ERbetacx as prognostic predictors in human prostatic
cancer. Biochem. Biophys. Res. Commun., 2001, 289(3), 692-699.
Wu, X.; Subramaniam, M.; Negron, V.; Cicek, M.; Reynolds, C.;
Lingle, W.L.; Goetz, M.P.; Ingle, J.N.; Spelsberg, T.C.; Hawse,
J.R. Development, characterization, and applications of a novel
estrogen receptor beta monoclonal antibody. J. Cell. Biochem.,
2011, 113(2), 711-723.
Pavao, M.; Traish, A.M. Estrogen receptor antibodies: specificity
and utility in detection, localization and analyses of estrogen
receptor alpha and beta. Steroids, 2001, 66(1), 1-16.
Celhay, O.; Yacoub, M.; Irani, J.; Dore, B.; Cussenot, O.; Fromont,
G. Expression of estrogen related proteins in hormone refractory
prostate cancer: association with tumor progression. J. Urol., 2010,
184(5), 2172-2178.
Lai, J.S.; Brown, L.G.; True, L.D.; Hawley, S.J.; Etzioni, R.B.;
Higano, C.S.; Ho, S.M.; Vessella, R.L.; Corey, E. Metastases of
prostate cancer express estrogen receptor-beta. Urology, 2004,
64(4), 814-820.
Zhu, X.; Leav, I.; Leung, Y.K.; Wu, M.; Liu, Q.; Gao, Y.; McNeal,
J.E.; Ho, S.M. Dynamic regulation of estrogen receptor-beta
expression by DNA methylation during prostate cancer
development and metastasis. Am. J. Pathol., 2004, 164(6), 20032012.
Torlakovic, E.; Lilleby, W.; Berner, A.; Torlakovic, G.; Chibbar,
R.; Furre, T.; Fossa, S.D. Differential expression of steroid
receptors in prostate tissues before and after radiation therapy for
prostatic adenocarcinoma. Int. J. Cancer, 2005, 117(3), 381-386.
Thelen, P.; Peter, T.; Hunermund, A.; Kaulfuss, S.; SeidlovaWuttke, D.; Wuttke, W.; Ringert, R.H.; Seseke, F. Phytoestrogens
from Belamcanda chinensis regulate the expression of steroid
receptors and related cofactors in LNCaP prostate cancer cells. BJU
Int., 2007, 100(1), 199-203.
Kim, I.Y.; Kim, B.C.; Seong, D.H.; Lee, D.K.; Seo, J.M.; Hong,
Y.J.; Kim, H.T.; Morton, R. A.; Kim, S.J. Raloxifene, a mixed
estrogen agonist/antagonist, induces apoptosis in androgen-
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
[84]
[85]
[86]
[87]
Current Molecular Pharmacology, 2012, Vol. 5, No. 3
399
independent human prostate cancer cell lines. Cancer Res., 2002,
62(18), 5365-5369.
Sasaki, M.; Tanaka, Y.; Perinchery, G.; Dharia, A.; Kotcherguina,
I.; Fujimoto, S.; Dahiya, R., Methylation and inactivation of
estrogen, progesterone, and androgen receptors in prostate cancer.
J. Natl. Cancer Inst., 2002, 94(5), 384-390.
Lau, K.M.; LaSpina, M.; Long, J.; Ho, S.M. Expression of estrogen
receptor (ER)-alpha and ER-beta in normal and malignant prostatic
epithelial cells: regulation by methylation and involvement in
growth regulation. Cancer Res., 2000, 60(12), 3175-3182.
Brolin, J.; Skoog, L.; Ekman, P. Immunohistochemistry and
biochemistry in detection of androgen, progesterone, and estrogen
receptors in benign and malignant human prostatic tissue. Prostate
1992, 20(4), 281-295.
Bouchal, J.; Santer, F.R.; Hoschele, P.P.; Tomastikova, E.;
Neuwirt, H.; Culig, Z. Transcriptional coactivators p300 and CBP
stimulate estrogen receptor-beta signaling and regulate cellular
events in prostate cancer. Prostate, 71(4), 431-437.
Hobisch, A.; Hittmair, A.; Daxenbichler, G.; Wille, S.; Radmayr,
C.; Hobisch-Hagen, P.; Bartsch, G.; Klocker, H.; Culig, Z.
Metastatic lesions from prostate cancer do not express oestrogen
and progesterone receptors. J. Pathol., 1997, 182(3), 356-361.
Hiramatsu, M.; Maehara, I.; Ozaki, M.; Harada, N.; Orikasa, S.;
Sasano, H. Aromatase in hyperplasia and carcinoma of the human
prostate. Prostate, 1997, 31(2), 118-124.
Nakamura, Y.; Suzuki, T.; Fukuda, T.; Ito, A.; Endo, M.; Moriya,
T.; Arai, Y.; Sasano, H. Steroid sulfatase and estrogen
sulfotransferase in human prostate cancer. Prostate, 2006, 66(9),
1005-1012.
Kawashima, H.; Nakatani, T., Involvement of estrogen receptors in
prostatic diseases. Int. J. Urol., 2012, 19(6), 512-522; author reply
522-523.
Sugiyama, N.; Barros, R.P.; Warner, M.; Gustafsson, J.A. ERbeta:
recent understanding of estrogen signaling. Trends Endocrinol.
Metab., 2010, 21(9), 545-552.
Takahashi, Y.; Perkins, S.N.; Hursting, S.D.; Wang, T.T. 17betaEstradiol differentially regulates androgen-responsive genes
through estrogen receptor-beta- and extracellular-signal regulated
kinase-dependent pathways in LNCaP human prostate cancer cells.
Mol. Carcinog., 2007, 46(2), 117-129.
Nakajima, Y.; Akaogi, K.; Suzuki, T.; Osakabe, A.; Yamaguchi,
C.; Sunahara, N.; Ishida, J.; Kako, K.; Ogawa, S.; Fujimura, T.;
Homma, Y.; Fukamizu, A.; Murayama, A.; Kimura, K.; Inoue, S.;
Yanagisawa, J. Estrogen regulates tumor growth through a
nonclassical pathway that includes the transcription factors ERbeta
and KLF5. Sci. Signal., 2011, 4(168), ra22.
Dondi, D.; Piccolella, M.; Biserni, A.; Della Torre, S.;
Ramachandran, B.; Locatelli, A.; Rusmini, P.; Sau, D.; Caruso, D.;
Maggi, A.; Ciana, P.; Poletti, A. Estrogen receptor beta and the
progression of prostate cancer: role of 5alpha-androstane3beta,17beta-diol. Endocr. Relat. Cancer, 2010, 17(3), 731-742.
Guerini, V.; Sau, D.; Scaccianoce, E.; Rusmini, P.; Ciana, P.;
Maggi, A.; Martini, P.G.; Katzenellenbogen, B.S.; Martini, L.;
Motta, M.; Poletti, A. The androgen derivative 5alpha-androstane3beta,17beta-diol inhibits prostate cancer cell migration through
activation of the estrogen receptor beta subtype. Cancer Res., 2005,
65(12), 5445-5453.
Leung, Y.K.; Gao, Y.; Lau, K.M.; Zhang, X.; Ho, S.M. ICI
182,780-regulated gene expression in DU145 prostate cancer cells
is mediated by estrogen receptor-beta/NFkappaB crosstalk.
Neoplasia, 2006, 8(4), 242-249.
Ball, L.J.; Levy, N.; Zhao, X.; Griffin, C.; Tagliaferri, M.; Cohen,
I.; Ricke, W.A.; Speed, T.P.; Firestone, G.L.; Leitman, D.C. Cell
type- and estrogen receptor-subtype specific regulation of selective
estrogen receptor modulator regulatory elements. Mol. Cell.
Endocrinol., 2009, 29 (2), 204-211.
Pandini, G.; Genua, M.; Frasca, F.; Squatrito, S.; Vigneri, R.;
Belfiore, A. 17beta-estradiol up-regulates the insulin-like growth
factor receptor through a nongenotropic pathway in prostate cancer
cells. Cancer Res., 2007, 67(18), 8932-8941.
Bouchal, J.; Santer, F.R.; Hoschele, P.P.; Tomastikova, E.;
Neuwirt, H.; Culig, Z. Transcriptional coactivators p300 and CBP
stimulate estrogen receptor-beta signaling and regulate cellular
events in prostate cancer. Prostate, 2011, 71(4), 431-437.
400 Current Molecular Pharmacology, 2012, Vol. 5, No. 3
[88]
[89]
[90]
[91]
[92]
[93]
[94]
Nakamura et al.
Bidosee, M.; Karry, R.; Weiss-Messer, E.; Barkey, R.J. Growth
hormone affects gene expression and proliferation in human
prostate cancer cells. Int. J. Androl., 2011, 34(2), 124-137.
Nanni, S.; Benvenuti, V.; Grasselli, A.; Priolo, C.; Aiello, A.;
Mattiussi, S.; Colussi, C.; Lirangi, V.; Illi, B.; D'Eletto, M.;
Cianciulli, A.M.; Gallucci, M.; De Carli, P.; Sentinelli, S.;
Mottolese, M.; Carlini, P.; Strigari, L.; Finn, S.; Mueller, E.;
Arcangeli, G.; Gaetano, C.; Capogrossi, M.C.; Donnorso, R.P.;
Bacchetti, S.; Sacchi, A.; Pontecorvi, A.; Loda, M.; Farsetti, A.
Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the
activation of a prognostic transcriptional pattern in aggressive
human prostate cancer. J. Clin. Invest., 2009, 119(5), 1093-108.
Lin, C.Y.; Strom, A.; Li Kong, S.; Kietz, S.; Thomsen, J.S.; Tee,
J.B.; Vega, V.B.; Miller, L.D.; Smeds, J.; Bergh, J.; Gustafsson,
J.A.; Liu, E.T. Inhibitory effects of estrogen receptor beta on
specific hormone-responsive gene expression and association with
disease outcome in primary breast cancer. Breast Cancer Res.,
2007, 9(2), R25.
Chang, E.C.; Frasor, J.; Komm, B.; Katzenellenbogen, B.S. Impact
of estrogen receptor beta on gene networks regulated by estrogen
receptor alpha in breast cancer cells. Endocrinology, 2006, 147(10),
4831-4842.
Grubisha, M.J.; Cifuentes, M.E.; Hammes, S.R.; Defranco, D.B. A
local paracrine and endocrine network involving TGFbeta, Cox-2,
ROS, and estrogen receptor beta influences reactive stromal cell
regulation of prostate cancer cell motility. Mol. Endocrinol., 2012,
26(6), 940-954.
Prossnitz, E. R.; Oprea, T. I.; Sklar, L. A.; Arterburn, J. B., The ins
and outs of GPR30: a transmembrane estrogen receptor. J. Steroid
Biochem. Mol. Biol. 2008, 109 (3-5), 350-3.
Chan, Q.K.; Lam, H M.; Ng, C F.; Lee, A Y.; Chan, E S.; Ng,
H.K.; Ho, S.M.; Lau, K.M. Activation of GPR30 inhibits the
growth of prostate cancer cells through sustained activation of
Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction
Received: October 15, 2012
[95]
[96]
[97]
[98]
[99]
[100]
[101]
of G(2) cell-cycle arrest. Cell Death Differ., 2010, 17(9), 15111523.
Filardo, E.J.; Quinn, J.A.; Bland, K.I.; Frackelton, A.R. Jr.
Estrogen-induced activation of Erk-1 and Erk-2 requires the G
protein-coupled receptor homolog, GPR30, and occurs via transactivation of the epidermal growth factor receptor through release
of HB-EGF. Mol. Endocrinol., 2000, 14(10), 1649-1660.
Revankar, C.M.; Cimino, D.F.; Sklar, L.A.; Arterburn, J.B.;
Prossnitz, E.R. A transmembrane intracellular estrogen receptor
mediates rapid cell signaling. Science, 2005, 307(5715), 16251630.
Thomas, P.; Pang, Y.; Filardo, E.J.; Dong, J. Identity of an estrogen
membrane receptor coupled to a G protein in human breast cancer
cells. Endocrinology, 2005, 146(2), 624-632.
Vivacqua, A.; Bonofiglio, D.; Albanito, L.; Madeo, A.; Rago, V.;
Carpino, A.; Musti, A.M.; Picard, D.; Ando, S.; Maggiolini, M.
17beta-estradiol, genistein, and 4-hydroxytamoxifen induce the
proliferation of thyroid cancer cells through the g protein-coupled
receptor GPR30. Mol. Pharmacol., 2006, 70(4), 1414-1423.
Vivacqua, A.; Bonofiglio, D.; Recchia, A.G.; Musti, A.M.; Picard,
D.; Ando, S.; Maggiolini, M., The G protein-coupled receptor
GPR30 mediates the proliferative effects induced by 17betaestradiol and hydroxytamoxifen in endometrial cancer cells. Mol.
Endocrinol., 2006, 20(3), 631-646.
Albanito, L.; Madeo, A.; Lappano, R.; Vivacqua, A.; Rago, V.;
Carpino, A.; Oprea, T. I.; Prossnitz, E.R.; Musti, A.M.; Ando, S.;
Maggiolini, M. G protein-coupled receptor 30 (GPR30) mediates
gene expression changes and growth response to 17beta-estradiol
and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer
Res., 2007, 67(4), 1859-1866.
Teng, J.; Wang, Z.Y.; Prossnitz, E.R.; Bjorling, D.E. The G
protein-coupled receptor GPR30 inhibits human urothelial cell
proliferation. Endocrinology, 2008, 149(8), 4024-4034.
Revised: December 25, 2012
PMID: 23302001
Accepted: January 3, 2013