CST1 Expression is Enriched in ERalpha-Positive Breast Cancer and Associated with ECM/CAF-Related Transcriptomic Features

CST1 has been experimentally linked to estrogen receptor alpha (ERalpha) signaling in breast cancer, but clinical-tissue and public-cohort evidence remains incompletely integrated. We investigated whether CST1 is enriched in ERalpha-positive tumors and whether its expression is associated with luminal and tumor-microenvironmental features.

CST1 immunohistochemistry (IHC) was analyzed in 179 unique breast cancers after exclusion of duplicate pathology identifiers, including 135 ERalpha-positive cases across four prespecified ERalpha-percentage strata and 44 mutually exclusive ERalpha-negative, triple-negative, or HER2-overexpression controls. External validation used TCGA-BRCA, METABRIC, and CPTAC-BRCA. TCGA data were analyzed for differential expression, coexpression, pathway enrichment, and curated module scores.

CST1 positivity was more frequent in ERalpha-positive tumors than in controls (101/135, 74.8% vs 11/44, 25.0%; odds ratio 8.91, 95% CI 4.06-19.54), and CST1 H-score was higher in the ERalpha-positive group. Public cohorts confirmed higher CST1 mRNA in ER-positive tumors and significant PAM50 subtype differences. Institutional IHC showed moderate separation of ERalpha-positive status (AUC 0.789), whereas transcriptomic AUCs were modest in TCGA-BRCA (0.596), METABRIC (0.562), and CPTAC-BRCA (0.693). In TCGA-BRCA, CST1-high tumors showed ECM/CAF-related coexpression, pathway-enrichment, and module-score patterns. In CPTAC-BRCA, CST1 correlated with ESTIMATE and xCell-derived stromal-enrichment scores. Because ER status, PAM50 subtype, and tumor purity may confound relationships between CST1 expression and stromal estimates, these exploratory bulk-tissue associations should be interpreted in the context of tumor subtype and tissue composition.

CST1 expression is enriched in ERalpha-positive breast cancer at the protein level and is reproducibly associated with ER/luminal features across public cohorts. Exploratory computational analyses further associate CST1 with ECM/CAF-related transcriptomic and stromal-enrichment features. However, potential confounding by ER status, PAM50 subtype, and tumor purity, together with the absence of spatial or functional validation, precludes independent or causal interpretation of the stromal associations.