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Commentaries |
From the Department of Adult Oncology, Dana Farber Cancer Institute, and the Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Estrogens, via the interaction with their receptors, play important roles in the control of cellular growth and differentiation. Specifically, estrogens regulate the growth and development of the mammary gland in embryogenesis as well as in pre- and postpubertal periods, and of ovarian follicles during the reproductive cycle.1 Importantly, estrogens are known to play a role in the development of the male reproductive system as well.2 The effects of estrogens on prostate epithelium are still primarily unknown although estrogens have been used in the treatment of prostate cancer because of their growth-inhibitory effects. However, either because of toxicity and/or because of poor response rates, treatment of prostate cancer with estrogen has been discontinued.
Estrogenic activity is mediated by the physical interaction between the estrogen receptors (ERs) and the hormone with subsequent activation of the receptors. These belong to a superfamily of nuclear receptors that are ligand-dependent transactivators and include receptors for retinoic acid, vitamin D, steroid, and thyroid hormones as well as orphan receptors for which ligands are yet to be found.3
Although it was initially thought that estrogens mediate their action
through a single receptor, the estrogen receptor 
(ER), a second
ER has been identified relatively recently from a rat prostate library
and termed ERß.4
Whereas these two receptors share
structural similarities (47% identity) and some functional properties,
it is clear that individual characteristics allow them to have distinct
biological functions.
Human ERs (hERs) have six functional regions that vary in their degree
of conservation. The least conserved region among species, within the
receptor superfamily and between ER and ERß, is the hypervariable
amino-terminal, important for transactivation. In contrast, the
DNA-binding domain is highly conserved (96% identity). Interestingly,
there is 59% identity at the amino-acid level between ER and ERß
in the ligand-binding domain. Although both receptors bind the natural
ligand 17ß estradiol with about equal affinity,5
phytoestrogens and selective estrogen receptor modulators (SERMs) can
bind ER and ERß selectively.6
However, the putative
diverse biological function of the two receptors should not only be
ascribed to different ligands but, more importantly, to their different
tissue distribution. When inactive, ERs exist as monomers bound to heat
shock proteins.7
On activation, they can form homodimers
(ER/ER; ERß/ERß) or heterodimers (ER/ERß). If, for
instance, ER and ERß are co-expressed in a given tissue or tumor,
the formation of a heterodimer will likely yield a different
transcriptional profile from that obtained if homodimers are generated
in the presence of natural ligands or SERMs.
Although androgens are required for the
normal development and function of the male reproductive system, the
role of estrogens is still unclear. ER, ERß, and ER/ß
knock-out mice have been generated to study the biological effects in
different tissues including the male reproductive
system.2,8-10
The main findings in these knock-out
strains are the requirement of ER for ovulation and that of ERß
for granulosa cell proliferation in the female, whereas male
infertility was found in the ER but not in the ERß knock-outs
(ßERKO). As far as the prostate is concerned, a recent
study10
reports no abnormalities in epithelial
proliferation in either ERß or double ER and ERß knock-outs
(ERßKO) despite previous reports suggesting such
abnormalities.9
The absence of prostatic lesions in the
ERß knock-outs does not contradict experimental evidence pointing to
a role for ERß as an inhibitor of prostatic growth, as suggested by
Leav and colleagues in this issue of The American Journal of
Pathology11
and by the same group of investigators in
another recent report.12
In fact, a case in point is that
of the cell-cycle inhibitor p27. p27 has been found to be associated
with aggressive behavior in a wide variety of tumors.13
Its targeted disruption in mice results merely in pituitary
tumors.14-16
However, when these mice are challenged by
carcinogens or radiation17
or are crossed with mouse
strains with known susceptibility to prostate cancer such as the PTEN
heterozygous-deficient mice,18
tumors develop at high
rates. Studies of this sort will prove useful in both ßERKO and
ERßKO genetically engineered strains to determine the putative
anti-proliferative function of ERß in the prostate.
The discovery of ER ß has thus lead to a re-evaluation of the biological functions of estrogens as well as of estrogen antagonists in prostate cancer. It has recently been shown that SERMs function as estrogens in some tissues whereas in others have anti-estrogenic effects.6 This is thought to result from the induction of distinct conformations in the two ERs, allowing the recruitment of different co-regulators. These, in turn, are thought to determine the transcriptional profile induced by ligands. In fact, opposite transcriptional events occur when the two receptors are exposed to tamoxifen in vitro.19 Thus, by defining the molecular mechanisms of ER signaling in prostate cancer cells it should be theoretically possible to design new SERMs with significant anti-tumoral activity.
Before antibodies became available, localization of the ER subtypes was
accomplished either by steroid autoradiography,20,21
in situ hybridization,22
or, more recently, by
reverse transcriptase-polymerase chain reaction.12,23
Therefore, in most of the studies ERß expression in both cell lines
and tissues has been investigated at the RNA level. Interestingly, only
ERß, and not ER transcripts were previously detected in rodent
prostate epithelial cells. ERß mRNA appeared to be expressed in both
basal and luminal cells.22
ER transcripts were also
found to be re-expressed after treatment with de-methylation agents in
human prostate cell lines suggesting transcriptional regulation of this
receptor.12
Again, at the RNA level, the prostate
carcinoma cell lines LNCaP and DU-145 were previously shown to express
exclusively ERß whereas PC-3 cells expressed transcripts from both
receptors.12
In addition, ERß transcripts were found to
be decreased in both localized and hormone refractory prostate cancers
relative to normal prostate tissue when these were measured by
quantitative reverse transcriptase-polymerase chain reaction,
suggesting that loss of ERß correlated with disease
progression.23
To date, several antibodies have been generated to the various regions
of ERß and used in Western blot analysis, immunoprecipitation, and
mobility shift assays.7
Some of these antibodies directed
at rat or mouse ERß10,24-27
or human
ERß28,29
have also been used in immunohistochemical
studies. In this issue, Leav and colleagues11
describe for
the first time the localization of the ERß protein in a spectrum of
human prostate specimens, ranging from normal, to dysplastic (prostate
intraepithelial neoplasia), to invasive and metastatic cancers. To
accomplish this, they generated a polyclonal antibody raised against a
peptide from the C-terminal region of the receptor. The peptide was
chosen on the basis of having no homology to the corresponding region
of ER. As far as normal tissue is concerned, ERß was found to be
expressed in basal cells of normal prostatic acini as well as in
stromal cells. Of note, ERß was not expressed in secretory cells.
Importantly, the only previous study in which ERß was detected in the
human prostate using an antibody raised against the N-terminus region
of the receptor, also localized ERß in basal acinar cells and in
stromal cells.29
As expected, ER was expressed only in stromal cell nuclei. Ho and
colleagues12
have also recently shown that primary,
nontransformed, human epithelial prostate cultures express ERß but
not ER mRNA. In this article,11
they confirm ERß
protein expression in prostate basal cells in culture (PrEC; Clonetics,
Inc. San Diego, CA).
Interestingly, Leav and colleagues11 show that high-grade dysplasia does not express ERß. Antiproliferative effects of tamoxifen and the anti-estrogen ICI-182,780 were previously shown to be reversed by ERß antisense in prostate cells.12 Furthermore, increased expression of ERß was found to be associated with estrogen-mediated protection from Apc-associated tumor formation in min mice.30 Finally, ERß protein down-regulation is associated with mitogenic activity in premalignant lesions of the breast.31 Taken together, these findings raise the attractive possibility that lack of expression of ERß may contribute to the initial phases of epithelial tumorigenesis. In terms of the early phases of prostate intraepithelial dysplasia, Leav and colleagues11 found expression of ERß in low-grade prostate intraepithelial neoplasia lesions but lack of expression in cells displaying high-grade dysplasia. Thus, ERß may be expressed in the very early phases of dysplasia (low grade), perhaps to counteract proliferative stimuli but lack of ERß expression occurs, and may in fact be required, in the lesions with high-grade cytological atypia, known to be associated with invasive carcinomas.
The pattern of expression in the invasive cancers examined was, as expected, more complex. Using the ERß-specific antibody they generated, Leav and colleagues11 showed that the majority of moderately differentiated tumors expressed ERß although a difference was observed when ERß-negative clear cell carcinomas of the transition zone were compared to ERß-positive tumors arising in the peripheral zone. ERß was also widely expressed in androgen-independent, metastatic tumors. Although obviously difficult to compare, the immunohistochemical findings seem to contradict the mRNA data previously reported in prostate cancer.23 However, little is known about posttranscriptional regulation of ERß and it may be possible that the ERß protein is more stable in androgen-independent, metastatic tumors despite reduced transcriptional activity for this gene. The finding of increased ERß in both moderately differentiated cancers and aggressive metastatic tumors is also contradictory. In essence, is ERß the good guy or the bad guy? Is its down-regulation associated with tumorigenesis and/or tumor progression or is the expression of ERß in prostate tumors of advanced stage transducing signals that favor tumor aggressiveness? Obviously, more detailed studies in human prostate cancer, complete of biochemical correlates, need to be performed to determine the precise role of ERß in these tumors.
The finding of positivity of tumor cells for ERß in metastatic, androgen-independent lesions, however, could be of potential therapeutic interest, provided the receptor is functional in this setting. To this end, it is interesting to note that many genes expressed by the basal cells, which do not depend on androgens for survival, such as bcl-2,32-34 Her-2-neu,35 and prostate stem cell antigen36 get re-expressed in advanced, androgen-independent cancers. Intriguingly, ERß seems to follow the same path. Except for the keratin profile and the almost universal expression of the androgen receptor in these tumors, metastatic, androgen-independent prostate tumors thus seem to display a basaloid phenotype. This should lend itself to targeted therapeutic manipulations of this late-stage, fatal type of prostate cancer, as Leav and colleagues11 suggest.
In summary, the different biological activities of ER and ERß, may
be ascribed to a variety of factors that will need to be carefully
studied in human prostate carcinomas now that tools such as laser
capture microdissection, quantitative real-time polymerase chain
reaction, and immunohistochemistry are available. These factors include
recruitment of different co-activators and co-repressors to modify
transcription and homodimeration versus heterodimerization
of these receptors. Because heterodimerization can only occur in cells
that co-express these receptors, assessment of expression of both ERs
as well as that of co-regulators, in normal and tumor tissues, becomes
of paramount importance. Leav and colleagues11
have begun
to address this issue in normal and neoplastic human prostate using a
novel, anti-hERß antibody. They have shown that ERß is expressed in
basal cells in normal prostatic acini, it is not expressed in
high-grade dysplasia, is expressed in the majority of moderately
differentiated, invasive cancers whereas it is lost with increasing
Gleason score. Interestingly, ERß was somewhat surprisingly expressed
in androgen-independent metastatic tumors. The data provided generate
more questions than they answer. In addition, one must bear in mind
that the number of cases assessed is small and that the antibody has
not been validated by other groups. Therefore, additional
immunohistochemical studies to assess ERß expression in prostate
cancer are necessary.
In conclusion, ERß may play a significant role in prostate cell differentiation and proliferation and may modulate both the initial phases of prostate carcinogenesis and androgen-independent tumor growth. Whether ERß enhances or suppresses prostate cancer development and/or progression remains to be established.
Footnotes
Address reprint requests to Massimo Loda, Dana Farber Cancer Institute, D-740, 44 Binney St., Boston, MA 02115. E-mail: massimo_loda{at}dfci.harvard.edu
Accepted for publication May 3, 2001.
References
and ß. Endocrinology 1997, 138:863-870 and ß. Steroids 2001, 66:1-16[Medline]
(ER) and ß (ERß) on mouse reproductive phenotypes. Development 2000, 127:4277-4291[Abstract]
and androgen receptor in normal human prostate glands, dysplasia, and in primary and metastatic carcinoma. Am J Pathol 2001, 159:79-92 and ER-ß in normal and malignant prostatic epithelial cells: regulation by methylation and involvement in growth regulation. Cancer Res 2000, 60:3175-3182 and ERß at AP1 sites. Science 1997, 277:1508-1510 (ER-) and ß (ER-ß) mRNA in the rat pituitary, gonad, and reproductive tract. Steroids 1998, 63:498-504[Medline]
and ER ß), and progesterone receptor expression in human prostate cancer by real-time quantitative reverse transcription-polymerase chain reaction assays. Cancer Res 2001, 61:1919-1926 knock-out and wild-type mice. Endocrinology 1998, 139:2982-2987 in the rat ovary. Endocrinology 1999, 140:963-971 and PR and associated with nodal status, grade, and proliferation rate in breast cancer. Am J Pathol 2000, 156:29-35 and ERß is associated with estrogen-mediated modulation of intestinal tumorigenesis. Cancer Res 2001, 61:2547-2551This article has been cited by other articles:
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