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Urology Research Mayo Clinic College of Medicine 200 First St SW
Rochester, MN 55905
Departments of Urology and Biochemistry Molecular Biology Mayo Clinic
College of Medicine 200 First St SW Rochester, MN 55905
In addition to androgens, estrogens play an important role in the normal
growth, development, and differentiation of the prostate. Estrogen action is
mediated through 2 receptor isoforms, estrogen receptor alpha (ER
) and
estrogen receptor beta (ERß). These receptors are structurally similar to
other nuclear receptors and share high homology in their DNA binding domains.
Less homology is observed between the ER and ERß amino terminal
(15.5%) and ligand binding (58%) domains, thus suggesting these ER isoforms
can mediate diverse biological functions
(Nilsson and Gustafsson, 2002;
Pearce and Jordan, 2004). A
role for estrogens in prostate carcinogenesis has been postulated, primarily
on the basis of epidemiologic observations and rodent studies
(Risbridger et al, 2003;
Harkonen and Makela, 2004;
Ho, 2004). However, the precise
significance of estrogens in prostate cancer development and progression
remains unclear.
Although estrogens may play a role in the development and progression of prostate cancer, it is well established that estrogens are effective inhibitors of prostate cancer cell growth (Ho, 2004). Indeed, the first application of hormone therapy employed the xenoestrogen, diethylstilbestrol (DES), to achieve prostate cancer regression (Huggins and Hodges, 1941). The primary result of this treatment is a reduction in circulating testosterone levels through the modulation of the hypothalamic-pituitary axis. However, more recent studies have shown that the administration of various ER ligands, including estrogens, anti-estrogens, phytoestrogens, and selective ER modulators (SERMs), also elicit a more direct suppression of prostate cancer growth (Ho, 2004). Many diverse mechanisms have been proposed to account for the direct anti-tumor effect of estrogens on prostate cancer cells (Ho, 2004). Initial clinical trials, however, have demonstrated that first-generation SERMs such as tamoxifen and toremifene are not effective treatments for ADI prostate cancer (Bergan et al, 1999; Stein et al, 2001).
One of the mechanisms through which ER ligands may directly inhibit
prostate cancer cell growth is the inhibition of AR-mediated transcriptional
activity (Kumar et al, 1994;
Panet-Raymond et al, 2000). The psa gene encodes the serine protease, prostate-specific antigen
(PSA), the best-characterized AR-regulated gene, and an important clinical
marker used to detect and monitor the progression of prostate cancer. Previous
studies have demonstrated that 17ß-estradiol (E2) can effectively inhibit
DHT-mediated, AR-dependent activation of androgen-responsive promoters such as
PSA and mouse mammary tumor virus long-terminal repeat
(Kumar et al, 1994; Panet-Raymond et al, 2000). A
further investigation demonstrated that this effect could be mediated through
a direct, ligand-mediated interaction between the carboxyl-terminal domain of
ER and the AR (Panet-Raymond et al,
2000).
In the current study, Zhu et al further examined the effects of ER ligands
on DHT-induced, AR-dependent PSA promoter activity. As has previously been
established, the authors observed that E2 could effectively inhibit
DHT-induced, AR-dependent PSA activation through ER but not ERß.
The pure estrogen antagonist, ICI-182780, was unable to block this effect.
However, the authors discovered that ICI-182780 treatment alone inhibited
DHT-induced, AR-dependent PSA activation to a similar degree as E2. To follow
up on this observation, the authors assessed the effects of DES, tamoxifen,
and 17-estradiol (E2, an isomer of E2 and a weak estrogen
agonist) in the same system. At high doses, DES had an inhibitory effect
similar to that of E2 and ICI-182780. The effects of these ligands were all
specifically mediated through ER. Tamoxifen, conversely, was unable to
modulate AR activity through ER, but it potentiated DHT-induced AR
activity through ERß. Interestingly, E2 effectively inhibited AR
activity through both ER and ERß. Thus, the effect of these ER
ligands on androgen action appears to be very different from their relative
estrogenic or anti-estrogenic activities.
To better understand the molecular basis for E2- and E2-mediated
inhibition of AR activity, the authors studied the effect of various truncated
forms of ER on DHT-induced, AR-dependent PSA activation. Surprisingly,
E2 and E2 displayed differential requirements for the ER DNA-
and ligand-binding domains, suggesting these ligands are able to inhibit the
AR via ER and/or ERß through distinct mechanisms. Nevertheless,
both E2 and E2 were equally effective at inhibiting DHT-stimulated
proliferation of LAPC-4 prostate cancer cells.
In normal prostate tissue, ERß is expressed primarily in the nuclei of
basal epithelial cells, while both ER and ERß are expressed in the
stroma (Leav et al, 2001). The
relative levels of ER and ERß in locally confined prostate tumors
are more variable, but it has been proposed that ERß levels decrease as
prostate cancer progresses locally (Horvath
et al, 2001; Leav et al,
2001; Pasquali et al,
2001). The majority of prostate cancer bone and lymph node
metastases, however, either predominantly or exclusively express ERß
(Leav et al, 2001). Perhaps the
most relevant and significant findings from this study, therefore, are that
E2 can inhibit DHT-induced AR activity through ERß and that
tamoxifen can potentiate DHT-induced AR activity through ERß. These data
could provide some explanation for the apparently contradictory data regarding
the role of estrogens in prostate carcinogenesis. It is also tempting to
speculate that these findings could in part explain the ineffectiveness of
tamoxifen as a therapy for ADI prostate cancer
(Bergan et al, 1999; Stein et al, 2001). Armed with
the knowledge provided in this study, it will be important in the future to
evaluate the ability of additional ERß ligands to inhibit AR activity.
This knowledge will be crucial to the proper design of clinical trials to test
the effectiveness of ERß ligands, including E2, as novel AR
inhibitors and potential treatments for ADI prostate cancer.
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Footnotes |
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References |
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 Top References |
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