Bladder cancer is an international public health problem. According to GLOBOCAN 2012, developed countries and parts of Africa displayed higher incidence rates, while countries of North Africa and the Middle East had the highest mortality rates [13]. It is also observed that the incidence of bladder cancer is much higher in males than females [14]. This difference in both genders as well as the disparity in the natural history of the disease needs further research.
A considerable amount of clinical data indicates that steroid hormone receptor-mediated signals compose a critical part in urothelial tumorigenesis and tumor progression. Examples of these receptors are androgen receptors, estrogen receptors, progesterone receptors, glucocorticoid receptors and retinoid receptors. Actually, studies on urothelial cancer samples have verified that raised or decreased expression of these receptors or modifications of their pathways relates to patient outcomes. Thus, steroid hormone receptors and associated signals may serve as biomarkers for urothelial carcinoma and can feasibly predict tumor recurrence or progression [15]. Several of these studies have revealed the possible role of AR signaling pathway and its co-regulators on the progression and development of urothelial cancers anticipating the usage of anti-AR therapies for urothelial cancer patients [16, 17].
In Egypt until recently, urinary bladder cancer has been a commonly diagnosed cancer [18]. Searching for a link between the AR pathway and the Egyptian population, we investigated the AR expression in urothelial carcinoma of the urinary bladder of Egyptian cancer patients. We found that AR was expressed in 29 (58%) of 50 evaluated tumors. This finding is close to that of Boorjian et al. [19] who reported AR expression in 53.1% of patients in their studied samples. However, different results were described by Miyamoto et al. [20], Nam et al. [9] and Mashhadi et al. [21] who detected the expression of AR in 42%, 37% and 22% of the bladder cancer patients, respectively. Such discrepancies between studies may be due to different staining conditions, criteria for over expression or patient populations.
In the current study, AR expression showed no statistically significant correlation with tumor grade (P = 0.07) and stage (P = 0.09). In this respect, it should be noted that previous studies that evaluated the relationship between AR and tumor aggressiveness of bladder cancer have led to conflicting results. For example, Tuygun et al. [12] reported a significant decrease in AR expression in higher grades and invasive tumors, which is consistent with the findings of Boorjian et al. [19]. In contrast, Mir et al. [22] showed that AR was elevated in muscle invasive tumors (15%) compared to non-muscle invasive ones (9%). In another study with 33 superficial bladder cancers, the authors concluded that patients with increased AR expression were more expected to have higher recurrence rates, compared to patients with lower AR expression [23]. Mashhadi et al. [21] detected a significant correlation between AR expression and high-grade and stage tumors. They also demonstrated higher rates of metastasis and lower relapse-free survival in AR positive patients compared to AR negative patients. In a different study, an inverse correlation was found between tumor grade and AR/androgen metabolizing enzymes expression [24].
Miyamoto et al. [20] stated that AR expression was significantly downregulated in high-grade muscle invasive tumors versus low-grade non-muscle invasive ones and found a significantly elevated expression of AR in lymph node metastasis as compared to primary tumors. In addition, it was found out that patients with AR positive muscle invasive tumors were apt to a higher risk of progression following radical cystectomy, although AR expression offered no prognostic discrimination regarding cancer-specific survival or tumor recurrence. Also, in another study, Ide et al. [15] reported that patients with AR positive non-muscle invasive tumors have a significantly lower risk of tumor recurrence compared to those with AR negative non-muscle invasive tumors, but not for disease progression.
A functional role for the AR in bladder cancer suggested that androgens inhibited bacilli Calmette–Guerin-induced interleukin-6 expression in bladder cancer cell lines expressing the AR and that androgen deprivation therapy reversed this effect [25]. In an alternative study, Boorjian et al. [19] did not measure AR function directly, but they found that the localization of the AR to the nuclei of tumor cells implied that the ligand binding domain of the AR was intact and functional, as the AR was believed to translocate to the nucleus only after androgen binding.
Miyamoto et al. [23] investigated whether or not androgen regulates the progression of bladder cancer through AR. By means of cell proliferation assays and mouse xenograft models, they concluded that indeed androgen increased the growth of AR positive bladder cancer cells, while anti-androgen therapy inhibited cancer progression pointing out that proliferation of some bladder cancers was definitely androgen dependent. Additionally, they found out that AR knockdown using siRNA in AR-expressing bladder cancer cell lines also reduced cell proliferation, even in androgen-depleted environment, raising the possibility that AR signals (through androgen-mediated and non-androgen-mediated mechanisms) might contribute to the promotion of bladder cancer progression. Furthermore, a prior in vivo study concluded that androgen-mediated AR signals can promote bladder carcinogenesis via down regulation of UDP-glucuronosyltransferases expression [26]. Also, it was found that conditional expression of AR increased the susceptibility to bladder cancer in mice [27].
