Cancer of the Prostate: Molecular Genetics
209
can occur in the amino-terminal domain
(exon 1), DNA-binding domain (exons 2 to
3), and hinge region (exon 4). Mutations
in the AR and overexpression may provide
the cells with a means of continued growth
despite low androgen conditions, a sensiti-
zation of the AR pathway. Other means of
sensitizing the pathway include activation
of AR in a ligand-independent manner by
growth factors and cytokines or ampliFca-
tion of coactivators. ±inally, some prostate
cancer cells have bypassed the AR pathway
altogether. A recent study demonstrated
the important roles of AR-associated pro-
tein 55 (dARA55) coregulator in the AR-
mediated growth of prostate cancer and
thus provided evidence that AR function
could be suppressed without mutation or
change in AR itself.
Overall, the AR plays an important
role in prostate cancer recurrence.
AR
ampliFcation may lead to continued stim-
ulation
with
low,
residual
androgens,
whereas
AR
mutations can alter recep-
tor speciFcity. New reports document an
important role of AR coactivators in by-
passing traditional methods of androgen
ablation. A better understanding of the
mechanisms of AR-dependent and AR-
independent growth will improve current
and target future methods of androgen
manipulation in prostate cancer. Polymor-
phisms in other genes of the androgen-
signaling cascade may contribute to the
racial and ethnic differences in prostate
cancer incidence and biologic behavior.
3
β
-hydroxysteroid dehydrogenase (type 2)
(
HSD3B2)
is involved in the catabolism of
dihydrotestosterone. Twenty-Fve alleles of
the (TG)n(TA)n(CA)n dinucleotide repeat
in the
HSD3B2
gene have been identi-
Fed, with the 289-bp form being the most
common. The shorter 275-bp allele was
more common in Blacks, and longer alleles
(281-bp, 302 to 340 bp) were more com-
mon in European-Americans and Asians.
A similar polymorphism exists in the 3
0
untranslated region of the 5
α
-reductase
type 2 gene (
SRD5A2
), whose product con-
verts testosterone to dihydrotestosterone.
The most common allele is the (TA)0 form,
without TA repeats, found in a majority of
men, whereas the two other alleles are
less frequent ((TA)9, (TA)18). Blacks pos-
sessed the (TA)18 allele in 18% of cases
studied; this allele was not found in Asian
or White populations. In addition to report-
ing the epidemologic Fnding of increased
risk of cancer in Black and Hispanic men
with the A49T missense substitution in
SRD5A2
, one study found high enzymatic
activity of the A49T variant in an
in vitro
,
mammalian system. It is thought that
the
HSD3B2
and
SRD5A2
polymorphisms
result in increased prostatic levels of di-
hydrotestosterone and therefore increased
risks of prostate cancer. Additional func-
tional and
in vivo
studies are necessary to
substantiate this hypothesis.
12
Conclusions
A wide variety of genetic alterations are
potentially involved in prostate carcino-
genesis. An improved understanding of
the molecular basis will improve screen-
ing of patients at high risk for tumor,
allow more accurate assessment of prog-
nosis prior to and after initial therapy, and
direct research toward novel and rational
treatment strategies.
See also
Genetics, Molecular Basis
of; Medicinal Chemistry.
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