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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., Competing Interests: Declaration of interests The following authors report current employment: Eli Lilly (B.J.), Shasqi, Inc (M.A.), GenieUsGenomics (A.T.), Morrison & Foerster LLP (A.G.), AstraZeneca (M.B.E. and L.E.S.), Odyssey Therapeutics (J.D.J.). K.P. serves on the Scientific Advisory Boards (SABs) of Novartis, Ideaya Biosciences, and Scorpion Therapeutics; holds equity options in Scorpion Therapeutics and Ideaya Biosciences; and receives sponsored research funding from Novartis, where she consults. F.M. is a cofounder of and has equity in Harbinger Health, has equity in Zephyr AI, and consults for Harbinger Health and Zephyr AI. She is on the board of directors of Exscientia Plc. She declares that none of these relationships are directly or indirectly related to the content of this manuscript. P.S. is a consultant for Novartis, Genovis, Guidepoint, The Planning Shop, ORIC Pharmaceuticals, Cedilla Therapeutics, Syros Pharmaceuticals, Blueprint Medicines, Curie Bio, Differentiated Therapeutics, Excientia, Ligature Therapeutics, Merck, Redesign Science, Sibylla Biotech, and Exo Therapeutics; he receives research funding from Novartis. A.G.L. serves on the SAB of Flash Therapeutics, Zentalis Pharmaceuticals, and Trueline Therapeutics and consults for AbbVie. M.B. receives research funding from Novartis, where he also serves on the SAB and acts as a consultant. He is a member of the SAB for Kronos Bio and GV20 Therapeutics and holds equity in both companies. He also serves on the SAB for FibroGen and is a consultant for Belharra Therapeutics. K.W.W. serves on the SAB of TScan Therapeutics, SQZ Biotech, Bisou Bioscience Company, DEM BioPharma, and Nextechinvest; receives sponsored research funding from Novartis; and is a co-founder, stockholder, and advisory board member of Immunitas Therapeutics. D.D. receives research support from Canon, Inc. H.W.L. receives research funding from Novartis., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)