Heterogeneity and transcriptional drivers of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes and subtype-driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single-cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs share features with mesenchymal neuroblastoma and rhabdoid tumors and that the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming super-enhancer landscapes, but it is not required for mesenchymal state maintenance or for cellular viability. Our comprehensive, large-scale, multiplatform, multiomics study of both experimental and clinical TNBC is an important resource for the scientific and clinical research communities and opens venues for future investigation. [Display omitted] •Major transcriptional and super-enhancer subtypes of triple-negative breast cancer (TNBC)•Multiomics factor analysis of TNBC epigenetic, functional, and clinical heterogeneity•PRRX1 is a main transcriptional regulator of mesenchymal TNBC subtype Jovanović et al. define the cellular, molecular, and functional heterogeneity of TNBC and integrated these using multiomics factor analysis into clinically relevant subtypes. Luminal, basal, and mesenchymal gene expression and super-enhancer subtypes do not match DNA methylation, histone modification, and metabolic patterns. PRRX1 is a central transcription factor in mesenchymal TNBC.