of androgen receptor in prostate cancer
Suzuki, Haruo Ito
of Urology, Chiba University School of Medicine 1-8-1 Inohana, Chuo-ku,
Chiba-shi, Chiba 260-8670, Japan
Asian J Androl 1999 Sep; 1: 81-85
AbstractThe growth of prostate cancer is sensitive to androgen, and hormonal therapy has been used for treatment of advanced cancer. About 80% of prostate cancers initially respond to hormonal therapy, howerver, more than half of the responders gradually become resistant to this therapy. Changes in tumors from an androgen-responsive to an androgen-unresponsive state have been widely discussed. Since androgen action is mediated by androgen receptor (AR), abnormalities of AR is believed to play an important role of the loss of androgen responsiveness in prostate cancer. This article focused on the role of AR in the progression of prostate cancer.
1 Loss of hormone sensitivity of prostate cancer
embryogenesis and puberty, androgens play an important role in the development
of the male phenotype in genotypical 46, XY individuals.
In adult males, they also control the function and structure of the male
urogenital tissues, including the prostate. In the prostate, the enzyme
5-reductase type 2 is responsible for conversion of testosterone to
the more potent 5-dihydrotestosterone. The action of both testosterone
and 5-dihydrotestosterone is mediated by the intracellular androgen
2 Structure and function of the AR
AR is a member of the family of nuclear receptors including the steroid
hormone receptors and other ligand-dependent transcription factors like
thyroid hormone receptors
and retinoic acid receptors. Steroid hormone receptors are characterized
by a central DNA binding domain, that targets the receptor to specific
DNA sequences (hormone responsive elements), a carboxy-terminal ligand
binding domain, and an amino-terminal regulatory domain (Figure
1). The DNA binding domain and ligand binding domain are relatively
conserved among the various steroid hormone
1.Structure and functional domain of androgen receptor.
3 Overexpression of AR in prostate cancerVisakorpi et al found high-level AR amplification in 7 of 23 (30%) hormone-refractory prostate cancer cases and in none of the specimens taken from the same patients prior to therapy. However, almost all of the cases showing AR overexpression have received only surgical castration or the LH-RH agonist without the administration of antiandrogens. Thus, they have not received MAB therapy. From these results, the loss of androgen sensitivity in these cases were thought to be caused by the growth of cancer clones stimulated by the remaining androgen from the adrenal glands, suggesting the importance of MAB therapy.
4 AR gene mutations in prostate cancer tissue
initial impulse to deal with AR gene mutations in prostate cancer came
from the study of LNCaP cell line, derived from a metastatic lesion of
the lymph node of a prostate cancer patient. AR of this cell line was
reported to contain one mutation at codon 877 (Thr to Ala)[7,8].
The growth of LNCaP cells is stimulated in vitro by the addition of androgens,
estrogens, progestogens, and several
antiandrogens, indicating a widely responsive property of LNCaP cells.
in the AR gene have been detected in prostate cancer specimens in
about 10%-20% of cases with the general finding that the frequency of
mutation appears to
be higher in hormone-refractory, metastatic tumors compared with untreated
lower grade primary tumors[9,10]. Since the growth of early
stage prostate cancer appears to be mediated by wild-type AR, it appears
that receptor mutation may have a role in conferring growth advantage
to cells during progression. Functional analysis of several AR mutations
detected in hormone-refractory cancers showed
a widely responsive property like LNCaP cells (Table 1).
Therefore, AR gene mutation is thought to be one of the molecular mechanisms
for loss of androgen dependency of prostate cancer.
the observation that certain mutations can clearly alter AR ligand specificity,
AR mutation has been postulated as playing a key role in the antiandrogen
withdrawal syndrome. This phenomenon occurs in a subset
of patients experiencing relapse of tumor growth, measured by increasing
serum PSA concentration, after a long-term antiandrogen treatment. After
the cessation of antiandrogen treatment, symptoms improve, and serum PSA
level drops, suggesting that the antiandrogen is acting agonistically
in the tumor cells to promote growth. Our previous study
reported that in 2 of 4 patients who experienced an improvement after
antiandrogen withdrawal (out of
total 22 prostatic cancer patients), AR mutations occurred
during antiandrogen treatment. These mutations, which were identical to
the LNCaP cell AR mutation (T877A), were not observed in untreated tumors.
From these results, the antiandrogen withdrawal syndrome seems to
be caused by AR mutation.
1. Responsive properties of mutated AR detected in prostate cancer patients.
mutated ARs were found in the patients treated with flutamide.
5 Down-regulation of AR in endocrine therapy-resistant prostatic cancers
studies of AR for prostate cancer showed a heterogeneous expression of
AR in cancer tissues. AR was noted in not only normal prostate, benign
prostatic hypertrophy but also prostate cancers including endocrine therapy-resistant
cases. In prostate cancer tissues, the ratio of AR-positive cells was
related with histological grade (i.e., Gleason score). Also, comparison of
AR status before and
after endocrine therapy within the same patient showed the down-regulation
of AR during the loss of androgen responsiveness.
Although the exact mechanism for this down-regulation of AR is
still unclear, two possible pathways are described here.
of AR promotor region
many types of malignancies, DNA hypermethylation of some tumor suppressor genes
(ie, VHL, RB, p16/MTS1/CDK4I, etc.) has been found[14, 15].
A main target of the regional hypermethylation is normally unmethylated
CpG islands located in gene promotor regions. This hypermethylation correlates
with transcriptional repression that can serve as an alternative to coding
region mutations for inactivations of the genes. Also, hypermethylation
of CpG island located
at estrogen receptor promotor was found in breast cancer tissues. A recent
study by Jarrard et al showed that in vitro
DNA methylation of AR
promotor CpG island was associated with loss of AR expression in human
prostate cancer cells. Further study should be necessary for confirmation
of this hypothesis.
Involvement of co-regulators (co-factors)
co-regulators between AR and transcriptional complex have been cloned.
Yeh et alhave cloned ARA70 as a specific co-regulator
for AR and demonstrated that ARA70 functioned as 10 times transcriptional
activator in DU145, which is an AR-negative prostate cancer cell line,
in the presence of androgen. Figure
2 and Table 2 showed co-regulators related to AR. Although the main cause
of androgen insensitivity syndrome (AIS) is AR gene mutation,
small number of AIS
patients revealed no AR mutations. It is suggested that abnormality of
co-regulator may contribute to the down-regulation of AR expression in
AIS patients. Similar mechanism is suggested to occur in prostate cancer
as well. Further studies should be performed to clarify the functional
role of co-regulators in prostate cancer.
2. Co-regulators (co-factors) of AR
2. Co-regulators (co-factors) of AR.
Shorter CAG repeats in the N-terminal domain of AR
incidence of prostate cancer is highly variable among races. The
highest incidence is observed in black peoples and the lowest incidence
is observed in Asian
peoples. Several reports have shown that the shorter poly-glutamine and
polyglycine repeat length has been correlated with the higher transactivational
function or expression level of AR, which has been associated with the
higher risk of prostate cancer. Hardy et al found
a significant correlation between the reduced CAG repeat
length and the age at prostate cancer onset, suggesting that CAG repeat
length may impinge on mechanisms involved in tumor initiation but not
in progression of
the localized to advanced stage.
Kokontis JM, Liao S. Molecular action of androgen in the normal and neoplastic
prostate. Vitamin Hormone 1999; 55: 219-307.
to Prof. Haruo Ito, The President of Japanese Society of Andrology.