Date Published: March 31, 2017
Publisher: Public Library of Science
Author(s): Hiroki Ide, Satoshi Inoue, Hiroshi Miyamoto, Francisco X. Real.
Emerging preclinical evidence suggests the involvement of sex hormones and their receptor signals in the development and progression of bladder cancer. Meanwhile, previous studies have demonstrated conflicting results on the relationship between the status of sex hormone receptors in urothelial tumors and histopathological characteristics of the tumors or patient outcomes. We therefore conducted this meta-analysis to assess the clinicopathological impact of the expression of androgen receptor (AR) and estrogen receptors (ERs) in bladder cancer.
A comprehensive literature search in databases (i.e. PubMed, Web of Science, Cochrane) was performed for all immunohistochemical studies stained for AR, ERα, and/or ERβ in surgically resected bladder cancer specimens and analyzed for patient outcomes. We selected eligible studies in accordance with the PRISMA guidelines and analyzed data using R software.
A total of 2,049 patients from 13 retrospective studies were included in this meta-analysis. The difference in ERα expression between non-tumors and tumors was significant [odds ratio (OR) = 0.412; P<0.001], while those of AR (OR = 3.256; P = 0.336) or ERβ (OR = 0.580; P = 0.674) were not statistically significant. AR positivity in tumors was strongly correlated with gender (male vs. female: OR = 0.658; P = 0.027) or tumor grade (low-grade vs. high-grade: OR = 0.575; P<0.001). ERβ positive rates were significantly higher in high-grade (OR = 2.169; P<0.001) and muscle-invasive (OR = 3.104; P<0.001) tumors than in low-grade and non-muscle-invasive tumors, respectively. Survival analysis in patients with non-muscle-invasive bladder cancer revealed associations between AR expression and better recurrence-free survival [hazard ration (HR) = 0.593; P = 0.006) as well as between ERβ expression and worse recurrence-free (HR = 1.573; P = 0.013) or progression-free (HR = 4.148; P = 0.089) survivals. These data suggest down-regulation of ERα expression in bladder tumors, compared with non-neoplastic urothelial tissues. AR or ERβ expression was down- or up-regulated, respectively, in high-grade and/or muscle-invasive bladder cancers. Moreover, immunohistochemistry of AR/ERβ in surgical specimens may serve as prognosticators in patients with non-muscle-invasive bladder tumor.
Urinary bladder cancer is one of the most frequently diagnosed neoplasms, with an estimated 429,800 new cases and 165,100 deaths occurred in 2012 worldwide . Although patients initially with non-muscle-invasive (NMI) tumor generally display favorable prognosis, they, especially those with high-grade tumor, have a relatively high risk of tumor recurrence with progression to muscle invasion after transurethral resection even with currently available intravesical pharmacotherapy. On the other hand, those with muscle-invasive (MI) tumor often develop disease progression or metastasis despite undergoing more aggressive treatment modalities, such as radical cystectomy with or without neoadjuvant or adjuvant systemic chemotherapy. Therefore, identification of key molecules involving bladder cancer outgrowth is urgently required, which may successively provide novel tumor markers that predict the prognosis as well as novel targeted therapy in patients with bladder cancer.
IHC has detected AR protein signals in 13–55% of bladder or upper urinary tract urothelial tumors [19, 20, 36, 38–44, 49–51], which is significantly lower than the positive rates in normal/non-neoplastic urothelial tissues (58–86%) reported by most of respective comparative studies [36, 38, 40, 51]. However, at least three immunohistochemical studies have demonstrated no AR expression in normal urothelium [42, 43, 52]. Significant or insignificant down-regulation of AR expression in high-grade or MI urothelial carcinomas, compared with low-grade or NMI tumors, has also been found [19, 36, 38–40, 42, 44, 49–51]. However, several studies showed even slight increases in AR positivity in high-grade and/or MI tumors [20, 41, 51]. Furthermore, two studies each have suggested a considerable association of AR expression in bladder tumors with a higher risk of the progression of only MI disease  or both NMI and MI diseases  or a lower risk of the recurrence of NMI disease [42, 44], or no such strong association with the prognosis of patients with NMI or MI disease [40, 41].