Classification of triple-negative breast cancer based on pathway enrichment levels

Triple-negative breast cancer (TNBC) is highly heterogeneous in the stromal and immune microenvironment, genome integrity, oncogenic signatures, and metabolic processes. However, a classification of TNBC by combining these features remains lacking. Here we classified TNBC based on the enrichment levels of 14 pathways related to immune, stromal, oncogenic and metabolic signatures by unsupervised clustering. In three bulk tumor transcriptome datasets and a single cell RNA-Seq (scRNA-seq) dataset, we consistently identified four TNBC subtypes: Imm-E, Str-E, DR-E, and Met-E. Imm-E displayed the strongest immune signatures, the lowest intratumor heterogeneity (ITH), the highest global methylation levels, the lowest tumor purity, and the best prognosis. Str-E showed the strongest stromal signatures and TGF-β signaling. DR-E had the highest DNA repair activity, cell cycle activity, and genomic instability. Met-E demonstrated the strongest hormone metabolism and signaling, the highest ITH, the lowest genomic instability, and the worst prognosis. The subtyping of TNBC provides novel insights into tumor biology and clinical implications for this disease.