Association Between Estrogen Receptors and GATA3 in Bladder Cancer: A Systematic Review and Meta-Analysis of Their Clinicopathological Significance

Abstract

BackgroundEstrogen receptors alpha (ERα) and beta (ERβ) and the cooperating protein GATA-binding factor 3 (GATA3) have been implicated in bladder carcinogenesis and tumour progression. GATA3 and ER have been functionally linked in the establishment of luminal fate in breast tissue, but to date their relationship in bladder cancer has not been established. This information will be useful to advance diagnostic and prognostic markers.AimTo determine the relationship between the expression of ERα, ERβ and GATA3 in bladder cancer, disclose their prognostic and diagnostic value and their association with clinicopathological characteristics.MethodsA comprehensive literature search in PubMed database was performed for all immunohistochemical studies of ERα, ERβ and/or GATA3 in bladder cancer patients. We selected eligible studies in accordance with the PRISMA guidelines and evaluated methodological quality and risk of bias based on quality criteria from the reporting recommendations for tumour MARKer (REMARK) prognostic studies. Risk of bias assessment was performed using Review Manager 5. R software was used for all statistical analysis, the packages used were meta and dmetar for the standard meta-analysis, and netmeta for the network meta-analysis.ResultsThirteen studies were eligible for ERα, 5 for ERβ and 58 for GATA3 meta-analysis. Low grade tumours showed significantly lower ERα expression. GATA3 was widely expressed in bladder tumours, especially urothelial carcinomas, with higher expression of GATA3 in low grade and low stage tumours. Data was insufficient to determine the prognostic value of either ERα or ERβ, but GATA3-positivity was associated with higher recurrence free survival. A negative correlation between ERα or ERβ positivity and GATA3 expression was disclosed. Additionally, several sources of heterogeneity were identified, which can be used to improve future studies.ConclusionThe clinicopathological value of ERα and ERβ was inconclusive due to low availability of studies using validated antibodies. Still, this meta-analysis supports GATA3 as good prognostic marker. On the contrary, ERα-positivity was associated to higher grade tumours; while ERα and ERβ were inversely correlated with GATA3 expression. Considering that it has previously been shown that bladder cancer cell lines have functional ERs, this suggests that ERα could be activated in less differentiated cells and independently of GATA3. Therefore, a comprehensive analysis of ERα and ERβ expression in BlaCa supported by complete patient clinical history is required for the identification of BlaCa subtypes and subgroups of patients expressing ERα, to investigate if they could benefit from treatment with hormonal therapy.Systematic Review RegistrationProspero, CRD42021226836.

GATA3 Predicts the Tumor Microenvironment Phenotypes and Molecular Subtypes for Bladder Carcinoma

“…GATA3, standing for GATA binding protein 3, contains two GATA-type zinc fingers at the structural level and is closely associated with the progression of various cancers, including breast cancer ( 8 , 32 – 34 ). GATA3 can also be considered a sensitive and specific marker for urothelial carcinoma ( 35 ) and as a criterion for BLCA subtypes classification.…”

“…Although GATA3 is highly expressed in bladder cancer, its high expression may adversely inhibit the progression of tumor cells in BLCA ( 6 ). Meanwhile, the over-expression of GATA3 predicts a lower tumor stage and a lower tumor grade but a higher relapse-free survival rate ( 7 , 8 ). Such an imbalance between the over-expression profile of GATA3 in BLCA cancer tissues and the inhibitory function of GATA3 on bladder cancer cells may be explained by the ability of GATA3 to transform basal bladder cancer cells into luminal cells ( 7 , 9 , 10 ).…”

Expression of BCL2, TP53, FOXA1, and GATA3 in pTa bladder cancer recurrence

“…Overexpression and accumulation of TP53 is then a predictor of poor prognosis in advanced-stage bladder tumors (49). TP53 expression has also been found to be associated with disease recurrence (50). Also, a meta-analysis suggested that overexpression of TP53 in NIMBC patients treated with BCG could be associated with RFS (51).…”

Establishment of an optimized orthotopic bladder cancer model in mice

“…Although the metastatic organs did not have typical cancerous nodes, tiny cancerous nodes were found under the microscope. Previous studies of the association between oestrogen and BC have demonstrated some mechanisms [ 41 , 42 ]. Moreover, the epidemiology of BC and related mechanical studies have confirmed the phenomenon and mechanism [ 43 – 46 ].…”