Androgens in Health and Disease.pdf - E Library

Chapter 9/Androgen Signaling in Prostatic Neoplasia and Hyperplasia 165
Detection of Mutant AR in Prostate Cancer
There is considerable controversy concerning the frequency and nature of these
mutations in prostate cancer. Molecular analysis of the AR was conducted in 724 cases
of clinically detectable prostate cancer (see Table 1). In these 724 cancers, a total of
59 mutations (53 somatic mutations, 2 germline mutations, 4 changes of the polyQ
tract) were detected for an overall frequency of 8%. The stage of the disease was
described for 660 patients. Early-stage prostate cancer (i.e., stage A or B disease) is
rarely associated with mutations of AR (7 mutations [2 somatic mutations, 2 germline
mutations, and 3 changes of the polyQ tract] in 336 cases [frequency 0.6%]) (117–
128). Primary lesions from patients with more advanced prostate cancer (stages C and
D) are more likely to contain mutations of AR. However, the overall incidence is still
low (27 somatic mutations and 1 change of the polyQ tract in 238 cases [11.3%])
(88,91,92,96,117–119,121–124,126,127,129,130). Finally, the prevalence of AR
mutations is more substantial in metastatic prostate cancer [24 in 97 cases (24%)
(118,127,128,131–133)]. Thus, mutations of AR are not early events leading to neoplastic
degeneration of prostatic tissue, rather they are late developments that may
affect biologic behavior and/or response to treatment.
Takahashi and colleagues investigated latent prostate cancers for the prevalence of
AR mutations (see Table 2) (137). They suggested that inactivating mutations of AR,
which are frequent in latent prostate cancer in Japanese men and absent in American
men, might prevent the evolution of latent subclinical prostate cancer into a clinically
detectable entity. This difference in the prevalence of AR mutations may account for the
different incidence of prostate cancer among Americans and Japanese men.
Functional Consequences of AR Mutations in Prostate Cancer
Functional analyses of AR mutants detected in prostate cancer have characterized
several different phenotypes that may play different roles in the development of androgen-independent
disease.
MUTATIONS CAUSING “GAIN-OF-FUNCTION”
Androgen-receptor gain-of-function mutations also have been called “promiscuous
receptors” (138). The first AR gene mutation with gain-of-function was described in
the prostate cancer cell line LNCaP (95), and resulted from the replacement of T at 877
with A. Transfection studies with this receptor showed increased binding affinities for
progestens and estradiol. Transcription was activated by these ligands at concentrations
that were not sufficient for activation of the wild-type receptor. Interestingly, the
T877A AR mutant was also activated by antiandrogens such as hydroxyflutamide,
nilutamide, and cyproterone acetate, but not bicalutamide (139). A subset of other AR
mutations detected in prostate cancer exhibits a phenotype similar to the T877A variant
with enhanced transcriptional activation of AR by several ligands, including the
antiandrogens hydroxyflutamide (97,98,140) and nilutamide (97), weak agonists
like the adrenal precursors dehydroepiandrosterone (DHEA) and androstenedione
(98,140), the androgen metabolites androsterone and androstanediol (140), and the
glucocorticoid agonist cortisol (141).
Another interesting group of superactive mutants are located at the boundary between
the hinge and the LBD (residues 668–671) (94). Compared to wild-type AR, these receptors
are 2- to 10-fold more active than wild-type AR upon stimulation with DHT, E2, P,