Estrogen Receptor Beta (ERβ) Expression in Colorectal Cancer (CRC)-A Systematic Review and Meta-Analysis

Background: ERβ is an estrogen receptor isoform expressed in the normal human colon and has been proposed to act as a tumor suppressor gene. The loss of ERβ expression has been associated with advanced stages of CRC. The aim was to investigate the relationship between ERβ expression and CRC progression, quantifying the difference between tumor tissues and normal controls, and early-stage versus late-stage tumors. Methods: English Medical literature searches were conducted using PubMed, Embase, and Google Scholar up to 31 December 2025 according to PRISMA. Case-control studies comparing ERβ expression in CRC biopsy specimens with that in healthy controls were included. A meta-analysis was performed using Comprehensive Meta-analysis (Version 4). Pooled ORs and 95% confidence intervals were calculated using a random-effects model. Heterogeneity was assessed using the Cochrane Q test and the I² statistic. Publication bias was evaluated. Results: Six studies, representing 13 sub-studies, were selected according to the inclusion criteria, involving 1183 patients and 1000 normal mucosa/tumor early-stage patients. The OR for ERβ expression was 0.211 (95%CI: 0.122-0.363), significantly lower in advanced tumor stages than in normal mucosa and early tumor stages (p < 0.0001). Positivity rates were 76.40% in controls and early-stage tumor patients versus 51.31% in tumor patients (all stages). Heterogeneity was high (I² = 78%), but sensitivity analysis confirmed the robustness of the results. Publication bias was not significant. The studies used different methods and positivity cut-off values, with high heterogeneity, and were from only five countries, indicating the possibility of variation in results across other geographical areas or ethnic groups. Conclusions: ERβ expression is significantly lower in CRC tissues than in healthy controls and progressively decreases as the disease progresses. This finding underscores ERβ's potential role as a prognostic factor and highlights the viability of ERβ activation as a novel therapeutic strategy.