Abstract
ObjectiveEmerging 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.MethodsA 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.ResultsA 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.ConclusionsThese 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.
Highlights
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 [1]
Immunohistochemistry of androgen receptor (AR)/ERβ in surgical specimens may serve as prognosticators in patients with nonmuscle-invasive bladder tumor
We performed a computerized bibliographic search of the PubMed, Web of Science, and Cochrane library in February 2017 for publications after 2004 in order to find the articles demonstrating the results of immunohistochemistry (IHC) of sex hormone receptors (i.e. AR, ERα, and/or ERβ) in bladder cancer tissue specimens obtained by transurethral resection or cystectomy from patients who did not receive radiotherapy or systemic chemotherapy preoperatively
Summary
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 [1]. Various epidemiological and clinical studies have demonstrated that men have a substantially higher risk of bladder cancer, while women tend to have more aggressive tumors [1,2,3,4,5,6,7]. These observations have prompted research on sex hormone receptors, such as androgen receptor (AR) and estrogen receptors (ERs), in bladder cancer [8,9,10]. Estrogens likely exert both stimulatory and inhibitory actions on bladder cancer outgrowth, which may be cell-specific and/or dependent on the functional activity of ERα and ERβ [11, 12, 26,27,28,29,30,31,32]
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