Heterogeneity and transcriptional drivers of triple-negative breast cancer
Bojana Jovanović, Daniel Temko, Laura E. Stevens, Marco Seehawer, Anne Fassl, Katherine C. Murphy, Jayati Anand, Kodie Garza, Anushree C. Gulvady, Xintao Qiu, Nicholas W. Harper, Veerle W. Daniëls, Huang Xiao-Yun, Jennifer Y. Ge, Maša Alečković, Jason W. Pyrdol, Kunihiko Hinohara, Shawn B. Egri, Malvina Papanastasiou, Raga Vadhi, Alba Font‐Tello, Robert M. Witwicki, Guillermo Peluffo, Anne Trinh, Shaokun Shu, Benedetto Diciaccio, Muhammad B. Ekram, Ashim Subedee, Zachary T. Herbert, Kai W. Wucherpfennig, Anthony Letai, Jacob D. Jaffe, Piotr Siciński, Myles Brown, Deborah Dillon, Henry W. Long, Franziska Michor, Kornélia Polyák
Abstract
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.