Cell–cell junction gene signatures as subtype-specific prognostic biomarkers in breast cancer

Cell-cell junctions (CCJs) are essential for maintaining epithelial integrity, and adhesion-related molecules have long been implicated in breast cancer progression. However, the subtype-specific prognostic significance of CCJ-related gene expression patterns within individual intrinsic breast cancer subtypes has not been systematically characterized. We analyzed 179 genes annotated to the Gene Ontology term "cell-cell junction organization" (GO:0045216) across intrinsic breast cancer subtypes using the METABRIC and The Cancer Genome Atlas (TCGA) datasets. Subtype-specific prognostic CCJ genes were identified using multivariate Cox proportional hazards models for disease-specific survival and integrated into CCJ gene expression signatures. The prognostic performance was validated in an independent cohort (SCAN-B). Elevated CCJ signature scores were associated with poorer survival across subtypes, with particularly strong effects in Luminal B (LumB) and Basal-like (Basal) tumors. Person-year analyses indicated that high CCJ scores predicted an increased incidence of early recurrence (0-5 years) in these aggressive subtypes. Pathway enrichment analyses revealed that high-score tumors exhibited upregulation of extracellular matrix organization and matrisome-related pathways. Single-cell RNA sequencing further demonstrated that LumB CCJ genes (e.g., PARD6B, CDH3) were predominantly expressed in tumor epithelial cells, whereas the Basal CCJ signature reflected contributions from epithelial (e.g., MARVELD2) and endothelial (e.g., RAMP2) cells. Collectively, CCJ signatures stratify prognosis and capture subtype-specific cellular and microenvironmental features in breast cancer.