In 1992, Edwards et al.24 reported the allelic frequency distribution of AR CAG repeat size in different U.S. racial/ethnic populations as part of a larger survey of genetic variation in a series of different trimeric and tetrameric tandem repeats. Among African Americans, the frequency of AR alleles with fewer than 22 CAG repeats was 65% compared to 53% in Caucasians and 34% in Asian Americans. On the basis of these observations, Coetzee and Ross78 hypothesized that AR CAG repeat length might be associated with the higher risk of prostate cancer in African Americans and the intermediate and low risks in
Figure 16.3 Mechanism of androgen receptor (AR) activation by ligand-dependent pathways. Following synthesis, the AR exists in dynamic equilibrium between an immature state and an active form capable of binding high-affinity androgenic ligands via association/dissociation with a complex that includes heat-shock proteins (hsp), p23, and a tetra-tricopeptide (TPR) containing protein. Ligand binding results in the dissociation of this complex,
Figure 16.3 Mechanism of androgen receptor (AR) activation by ligand-dependent pathways. Following synthesis, the AR exists in dynamic equilibrium between an immature state and an active form capable of binding high-affinity androgenic ligands via association/dissociation with a complex that includes heat-shock proteins (hsp), p23, and a tetra-tricopeptide (TPR) containing protein. Ligand binding results in the dissociation of this complex, receptor dimerization and phosphorylation, nuclear transport, DNA binding, recruitment of components of the transcription machinery (TM) and other cofactor molecules (such as the p160 coactivators), and ultimately activation of androgen-regulated gene pathways. SHBG, sex hormone-binding globulin; DHT, dihydrotestosterone; CBP, cyclic adenosine monophosphate response element binding protein.
Caucasians and Asian Americans, respectively, and that enhanced transcriptional activity of receptors with a shorter AR CAG allele could promote tumorigenesis by enhancing prostatic epithelial cell turnover.
In 1995, the same investigators directly tested this hypothesis in a pilot case-control study comprising 68 prostate cancer patients and 123 control subjects.79 In agreement with Edwards et al.,24 there was a prevalence of short AR CAG alleles in African-American vs. Caucasian and Asian-American controls. In addition, modest, though not statistically significant, enrichment of short AR CAG alleles was observed in the Caucasian prostate cancer patients. These findings were extended in an expanded follow-up study, which showed a significantly higher prevalence of short AR CAG alleles among prostate cancer patients, especially those with advanced disease (Table 16.1).80 In addition to our studies, Hakimi et al.81 identified a subgroup of patients diagnosed with advanced prostate cancer who had shorter AR CAG repeats. Hardy et al.,82 furthermore, demonstrated an association between age at onset and AR CAG repeat length.
Subsequently, several well-designed, matched case-control studies demonstrated an approximately twofold increased prostate cancer risk, decreased age at onset, and/or increased risk of advanced disease for reduced AR CAG repeat length (Table 16.1). Giovannucci et al.25 used a population selected from the Physicians Health Study that included 587 prostate cancer cases and 588 matched controls. The large sample size allowed the stratification of cases by tumor grade and stage. A highly significant inverse correlation between AR CAG repeat length and risk of developing prostate cancer was observed when repeat size was analyzed as a semicontinuous variable. Short AR CAG alleles also correlated with increased risk of having advanced disease, defined as a high stage or high-grade tumor at diagnosis.25 Stanford et al.83 analyzed AR CAG repeat length and prostate cancer risk in 301 prostate cancer cases and 277 matched controls. They noted only a small increase in the frequency of AR CAG alleles with fewer than 22 repeats in cancer patients compared to controls. Nevertheless, when AR CAG repeat size was examined as a continuous variable, an overall age-
adjusted relative odds of developing prostate cancer of 0.97 was observed for each additional CAG. Hsing et al.84 reported that AR CAG al-leles were significantly shorter in prostate cancer patients compared to controls among Shanghai Chinese. This study was the first to demonstrate an association in a non-Caucasian population. In a case-control study in an Australian Caucasian population, no association was observed between AR CAG repeat length and prostate cancer risk, but a significant effect of age at onset was observed.85 In other studies (Table 16.1), associations between AR CAG repeat length and prostate cancer risk were not consistently observed, possibly due to small sample sizes, population differences, and/or failure to appropriately match cases and con-
While the epidemiological studies discussed above consistently provided evidence for an association between AR CAG repeat length and prostate cancer risk, they did not address the molecular mechanisms underlying changes in receptor activity. As stated above, in vitro transient cotransfection studies have shown that ARs with longer polyQ tracts (encoded by the polymorphic CAG repeat) have normal ligand-binding affinity but lower transactivation activ-ity.30-33,85 Protein expression levels are unlikely to account for this effect since they have been found to be similar for ARs containing 9-42 polyQ repeats.22 However, two studies have reported that AR constructs with longer repeat lengths (CAG-50 to CAG-52) are unstable and undergo accelerated degradation, potentially in a ligand-dependent manner.22,97 The polyQ size effect in AR transactivation activity observed in most in vitro studies is thought to be mediated, at least in part, through altered functional interactions with cofactors. In transient cotransfec-tion experiments, the p160 coactivators GRIP1, AIB1, and SRC-1 exaggerate the relative difference in AR transactivation activity with altered polyQ length.22 As the p160 coactivators bind to regions of the AR distinct from the polyQ tract, this effect may be mediated by steric hindrance of p160-receptor interactions when polyQ length is increased.22 The RAS-related G protein Ran/ARA24, which binds to the AR NTD in the polyQ region, is an AR cofactor that ap-
AR-CAG Repeat Associations
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