Sex Hormone Receptor Profiling Reveals an Association between Estrogen Receptor β-NRF2 Signaling and Improved Outcomes in Colorectal Cancer Patients

Background/Aims: Colorectal cancer (CRC) shows clear sex-related differences influenced by hormonal and molecular factors, with estrogen generally exerting a protective effect through estrogen receptor beta (ERβ). The nuclear factor erythroid 2-related factor 2 (NRF2) pathway, a key regulator of oxidative stress and immune responses, may interact with estrogen signaling; however, this relationship in CRC patients remains poorly understood. Methods: A total of 300 patients with histologically confirmed CRC, 37 patients with colorectal adenomas, and 35 control subjects were prospectively enrolled. Colonic tissue samples were subjected to immunohistochemical staining for ERα, ERβ, androgen receptor, and NRF2. The associations of ER expression with clinicopathological variables, tumor stage, and survival outcomes were evaluated using chi-square tests, Pearson correlation analysis, Cox proportional hazards regression models, and Kaplan-Meier survival analysis. Results: ERβ expression was significantly lower in patients with advanced-stage, metastatic, and poorly differentiated CRC, whereas higher ERβ expression was more frequent in those with right-sided and early-stage CRC and was associated with higher body mass indices and lower metastatic rates. High ERβ expression correlated with significantly improved overall and cancer-specific survival (p=0.005 and p=0.010, respectively). A strong positive correlation was observed between ERβ and NRF2 expression (r=0.717, p<0.001), suggesting a mechanistic link between estrogen signaling and antioxidative pathways. ERα expression was low and inconsistent, whereas androgen receptor expression correlated with a favorable survival trend but lacked independent prognostic value. Conclusions: High ERβ expression was associated with favorable tumor characteristics and improved survival in CRC, supporting a tumor-suppressive role potentially mediated through interaction with the NRF2 antioxidative pathway (ClinicalTrials.gov identifier: NCT05638542).