Androgen-receptor gene structure and function in prostate cancer

Abstract

Androgen-receptor (AR) gene mutations have been found in clinical prostate cancer, both prior to hormonal therapy and in hormone-refractory disease that persists despite androgen-ablative therapy. Thus, mutations that are present in late-stage disease might arise prior to therapy rather than as a result of therapy. A common feature of mutations in untreated prostate cancer and in hormone-refractory prostate cancer is that the AR retains activity as a ligand-dependent transcription factor. Some AR mutations in prostate cancer show broadened ligand specificity, such that the transcription-factor activity of the AR can be stimulated not just by dihydrotestosterone (DHT) but also by estradiol and other androgen metabolites that have a low affinity for the AR. The activation of mutant AR by estrogen and weak androgens could confer on prostate cancer cells an ability to survive testicular androgen ablation by allowing activation of the AR by adrenal androgens or exogenous estrogen. Such mutations might confer an advantage even prior to androgen ablation, since prostate cancer has lower levels of 5 alpha-reductase and, therefore, of DHT, than normal. Thus, AR mutations that occur prior to therapy may characterize a more aggressive disease. A large percentage of tumors appear to have no AR gene mutation. In tumors without an AR gene mutation, AR function might be affected via other mechanisms (e.g., AR gene amplification, which could increase the amount of AR activity at a given DHT level). Importantly, the apparent absence of AR gene mutations in the majority of earlystage tumors indicates that the role of androgen in the development of clinical prostate cancer is mediated predominantly by a normal AR gene. There are actually multiple alleles of the normal AR gene; these allelic variants differ in glutamine and glycine repeat length in the transactivation domain of the protein, and they may differ in signal-transducing activity. The glutamine and glycine repeat length may thereby modulate the effect of androgen on tumor-cell proliferation that occurs during clonal expansion.

CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk

“…Androgens are potent growth factors for the normal prostatic gland and are considered as important promoting factors for the development of prostatic adenocarcinoma (Hakimi et al, 1996). Circulating androgens diffuse into prostatic cells where they bind to the AR.…”

“…There is an inverse linear relation between CAG repeat length and AR transactivation function (Chamberlain et al, 1994;KazemiEsfarjani et al, 1995;Tut et al, 1997), in the upper extreme end (> 40 repeats) manifested as the rare Kennedy's disease with symptoms such as muscular atrophy, low virilization and subfertility (La Spada et al, 1991). Prostatic cells with short CAG repeats in the AR gene would consequently have increased sensitivity to proliferative stimulation of androgens, and the conditions for malignant growth would therefore be better (Hakimi et al, 1996). Interestingly, the frequency distribution of AR CAG repeat length in different races co-varies with prostate cancer incidence (Irvine et al, 1995).…”

Molecular and cellular biology of prostate cancer—the role of apoptosis as a target for therapy

“…22 The AR has been reported to be frequently modi®ed in patients with prostate cancer. 42 One of the key modi®cations may relate to a glutamine-repetitive sequence occurring in the receptor, which appears to vary in length among those of Asian descent, Caucasians and African men. 38 The length of a polymorphic CAG repeat sequence, occurring in the androgen receptor gene, has been shown to be inversely correlated with transcriptional activity by the AR, and the shortest repeats are thought to be associated with more aggressive cancers.…”

“…38 The length of a polymorphic CAG repeat sequence, occurring in the androgen receptor gene, has been shown to be inversely correlated with transcriptional activity by the AR, and the shortest repeats are thought to be associated with more aggressive cancers. 42,43 The trinucleotide expansion has been shown to affect the AR function for example, by weakening its transactivation properties), which is believed to confer variable androgenicity upon the prostate over time. 44 Therefore, it seems that the effect of androgen can either by increased or decreased depending on the properties of the AR, and this may represent a novel mechanism for androgen resistance.…”

The relationship between the androgen receptor CAG repeat polymorphism length and the response to intermittent androgen suppression therapy for advanced prostate cancer

“…3 Given that the length of the CAG repeat is inversely related to the transactivation function of the AR gene, 4,5 it has been suggested that a shorter CAG repeat length is associated with a greater risk of developing prostate cancer, as the increased response to the proliferative signalling by androgens may facilitate conditions for malignant growth. 6,7 The clinical evidence to support this relationship, however, is inconclusive. [8][9][10][11][12][13][14][15][16][17] Suzuki et al 18 found that a shorter CAG repeat length predicted for a better response to endocrine therapy.…”