Comparative Bioinformatics Characterization of IL6R Expression and Immune Associations in Breast Cancer and Uterine Corpus Endometrial Carcinoma

Background: The interleukin-6 receptor (IL6R) mediates classical and trans-signaling through the IL-6 pathway. Although IL-6/JAK/STAT signaling has been extensively investigated in breast cancer (BRCA) and uterine corpus endometrial carcinoma (UCEC), the consistency of bulk-tissue IL6R expression patterns and their clinical associations across these malignancies remain incompletely characterized. Methods: IL6R expression and its associations with clinicopathological characteristics, immune-cell infiltration, biological pathways, and survival outcomes were evaluated using TIMER, GEPIA, UALCAN, LinkedOmics, Kaplan–Meier Plotter, and patient-level TCGA data accessed through UCSC Xena. Independent expression validation and exploratory receiver operating characteristic (ROC) analyses were performed in GSE42568, GSE17025, and GSE63678. Multivariable Cox models assessed overall survival using continuous standardized IL6R expression with adjustment for age, pathological stage, and available tumor-subtype classifications. Results: TCGA-based analyses showed lower bulk IL6R expression in BRCA and UCEC tumors than in normal tissues, including comparisons involving Stage I tumors. Exploratory BRCA subclass analysis found expression differences involving TNBC after correction for six major-class comparisons. In both cancer types, IL6R expression showed positive correlations with several computationally estimated immune-cell populations. However, the strength and statistical significance of these correlations varied across immune-cell populations and between cancer types. Genes associated with IL6R were predominantly found in pathways related to immune and cytokine signaling. Independent GEO analysis supported significantly reduced IL6R expression in BRCA (GSE42568). In contrast, independent validation of IL6R downregulation was not consistently achieved in UCEC. The primary probe (205945_at) showed nonsignificant reductions in both UCEC datasets (GSE17025 and GSE63678), whereas the secondary probe (217489_s_at) showed significant upregulation in GSE17025 and no significant difference in GSE63678. These findings indicate that the TCGA-derived pattern of reduced IL6R expression in UCEC was not consistently reproduced in independent GEO cohorts. Exploratory ROC analyses produced AUCs of 0.736 (95% CI, 0.601–0.870) for GSE42568, 0.716 (95% CI, 0.602–0.830) for GSE17025, and 0.943 (95% CI, 0.810–1.000) for GSE63678. These estimates within cohorts do not demonstrate clinical diagnostic performance. In adjusted Cox models, continuous IL6R expression was not independently associated with overall survival in BRCA (HR, 1.02; 95% CI, 0.84–1.23; p = 0.846) or UCEC (HR, 0.93; 95% CI, 0.75–1.15; p = 0.513). Conclusions: TCGA-based analyses showed lower bulk-tissue IL6R expression in BRCA and UCEC tumors compared with corresponding normal tissues, with associations involving computationally estimated immune-cell populations. However, IL6R expression was not independently associated with overall survival. Independent GEO analyses supported IL6R downregulation in BRCA but did not consistently validate this pattern in UCEC, where the primary probe showed nonsignificant reductions in both cohorts and the secondary probe showed significant upregulation in GSE17025. Exploratory ROC analyses provided within-cohort estimates of tumor–normal discrimination but did not establish clinical diagnostic utility. Because soluble IL6R levels, IL6ST associations, and pathway activation were not measured, these findings cannot establish functional IL-6 signaling activity or a shift toward trans-signaling. The results should therefore be considered exploratory and hypothesis-generating, particularly for UCEC.