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  • In addition to differential expression

    2023-01-24

    In addition to differential expression of AR protein primarily in surgical specimens, genetic alterations involving the AR gene have been documented in human Myelin Basic Protein (87-99) cancer. Loss of heterozygosity at the AR locus was identified in all 3 informative cases of muscle-invasive bladder tumors, whereas, instead of allelic loss, non-random inactivation of the X chromosome where human AR gene locates was seen in concurrent lesions of carcinoma in situ from 2 of 3 female patients (Cheng et al., 2004). In addition, several studies have demonstrated differences in the number of polyglutamine (CAG) repeats within exon 1 of the AR gene, which in general is inversely correlated with its transcriptional activity, between bladder tumors and controls or different grades/stages of bladder tumors. Men and women who had 23 (odds ratio = 2.09) and 44 (cumulative; odds ratio = 4.95) CAG repeats, respectively, were found to have a significantly elevated risk of urothelial carcinoma, compared to those with longer CAG (Liu et al., 2008). A significantly shorter CAG repeat length was also identified in 95 male patients with bladder cancer (mean: 19.8), compared with 94 control males (mean: 21.1) (Teng et al., 2010). Furthermore, short CAG repeat lengths (20 in UMUC3 and 22 in TCCSUP) were detected in the 2 AR-positive human bladder cancer cell lines (Boorjian et al., 2009). Meanwhile, although a study involving 99 cases of bladder cancer showed no somatic mutations in the AR gene (Wu et al., 2013b), molecular profiling data search (Cerami et al., 2012, Gao et al., 2013) identified them in up to 4% (2 of 50) of urothelial carcinomas of the bladder as well as in 6.1% (2 of 33) of plasmacytoid urothelial carcinomas. AR isoforms (i.e. 90 kDa, 60 kDa) were also detected in some of tumor specimens (Zhuang et al., 1997), suggesting the presence of its splice variants in bladder cancer.
    AR signaling and urothelial carcinogenesis The sex-specific difference in the incidence of bladder cancer, as well as potential down-regulation of AR expression in urothelial tumors compared with non-neoplastic urothelial tissues, implies the involvement of androgen-mediated AR signaling in urothelial tumorigenesis. High incidence of prostatic adenocarcinoma in cystoprostatectomy specimens undergone for bladder urothelial carcinoma [e.g. 24.4% in a meta-analysis involving 13,140 patients (Fahmy et al., 2017)] may also support the presence of common pathway(s) for the development of these 2 malignancies, as AR is known to play an important role in prostate tumorigenesis. Previous studies using various approaches have indeed assessed the role of androgens and/or AR in urothelial carcinogenesis. N-butyl-N-4-hydroxybutyl nitrosamine (BBN), a chemical carcinogen known to induce bladder tumor effectively in rodents and more rapidly in males than in females (Bertram and Craig, 1972), have often been used to assess the effects of androgens and anti-AR therapies on bladder tumorigenesis. In earlier studies, testosterone administration in BBN-treated female rats was shown to increase the incidence of bladder tumors (Bertram and Craig, 1972, Okajima et al., 1975). Androgen deprivation therapy, including surgical castration, chemical castration via diethylstilbestrol or luteinizing hormone-releasing hormone analogue treatment, or an anti-androgen flutamide treatment, in male animals has also been found to inhibit BBN-induced tumor development (Bertram and Craig, 1972, Imada et al., 1997, Miyamoto et al., 2007, Okajima et al., 1975). In addition, early castration at 4 weeks of age prolonged the survival of BBN-treated male mice, suggesting a promoting effect of androgens on early stages of bladder carcinogenesis (Zhang et al., 2015). However, treatment with a 5α-reductase inhibitor finasteride did not reduce the occurrence of bladder tumors in this model (Imada et al., 1997), suggesting testosterone is a potent androgen to induce bladder tumorigenesis. Subsequently, BBN was shown to completely fail to induce bladder cancer in male or female AR knockout (ARKO) mice (Miyamoto et al., 2007). These findings indicate that androgen-mediated AR signals play a critical role in bladder carcinogenesis induced by a chemical carcinogen. However, a subset of male ARKO mice treated with BBN and supplemented with dihydrotestosterone (DHT) developed bladder tumors (Miyamoto et al., 2007). Thus, the differences in the incidence of BBN-induced bladder cancer between castrated males (50% at 40 weeks) versus ARKO males (0%) and between DHT-supplemented ARKO males (25%) versus ARKO males/females (0%) (Miyamoto et al., 2007) suggest the involvement of non-androgen- or low levels of androgen-mediated AR pathways and androgen-mediated non-AR pathways, respectively, in bladder tumorigenesis. Otherwise, androgen effect on bladder tumorigenesis in ARKO mice might be mediated through the truncated AR protein that is unable to bind to DNA, because only DNA-binding domain in exon 2 of the AR gene was disrupted in these animals (Yeh et al., 2002). More recently, BBN was also found to fail to induce bladder tumors in male mice having normal levels of testosterone yet lacking AR specifically in their urothelium generated by the mating of uroplakin II promoter-driven Cre male and flox-AR female mice (Hsu et al., 2013). An anti-AR agent, ASC-J9 that could selectively degrade AR protein via dissociation of AR and AR co-regulators (Yang et al., 2007), also strongly prevented the development of bladder tumors in the urothelium-specific ARKO male mice, presumably via modulating p53 activity (Hsu et al., 2013). Similarly, the incidence of BBN-induced bladder tumor was higher in a transgenic mouse model where AR is conditionally expressed in the bladder urothelium (R26hAR:Upk3a) than in the age and sex matched control littermates (Johnson et al., 2016). In another transgenic model in which constitutively active β-catenin in the urothelial basal cells could spontaneously induce high-grade urothelial cancer, tumor development was suppressed by orchiectomy (Lin et al., 2013). All these studies, using transgenic animal models, further suggest a critical role of urothelial AR, but not ARs in other organs, in bladder carcinogenesis.