Androgen receptor expression is associated with a distinct low-proliferative phenotype in triple-negative breast cancer

Abstract Background AR-related molecular subtypes, such as the luminal androgen receptor (LAR) subtype, exhibit distinct biological phenotypes in triple-negative breast cancer (TNBC), but the significance of AR expression as a single gene, particularly at single-cell resolution, remains incompletely understood. Methods We analyzed four bulk TNBC cohorts (TCGA, n = 170; METABRIC, n = 335; SCAN-B, n = 174; ORIEN, n = 483) and two single-cell RNA-sequencing cohorts (GSE246613, n = 21; Xu et al., n = 26). Bulk analyses evaluated molecular subtypes, proliferation-related pathways, genomic features, immune-cell abundance, and survival. Single-cell analyses assessed epithelial cell states, pathway activity, cell-cycle characteristics, and cell–cell communication. Results AR-high tumors were enriched for LAR and molecular apocrine subtypes and had lower histologic grade. AR-expressing epithelial cells showed reduced proliferative activity, with greater G1-phase representation and lower S- and G2M-phase activity. Consistently, AR-high tumors showed lower MKI67 expression and reduced proliferation-related pathway activity. AR-high tumors also had fewer TP53 mutations and more PIK3CA mutations. TGFβ-related activity was increased in AR-expressing epithelial cells, while AR-high tumors showed distinct immune-cell composition, including lower estimated Th1/Th2 abundance and higher M2 macrophage abundance. AR expression was not independently associated with survival. Conclusions AR expression identifies a distinct, low-proliferative biological state in TNBC characterized by altered cell-cycle activity, genomic features, enhanced TGFβ-related signaling, and a specific immune-cell composition.