TRPS1 Is a Lineage-Specific Transcriptional Dependency in Breast Cancer

Perturbed epigenomic programs play key roles in tumorigenesis, and chromatin modulators are candidate therapeutic targets in various human cancer types. To define singular and shared dependencies on DNA and histone modifiers and transcription factors in poorly differentiated adult and pediatric cancers, we conducted a targeted shRNA screen across 59 cell lines of 6 cancer types. Here, we describe the TRPS1 transcription factor as a strong breast cancer-specific hit, owing largely to lineage-restricted expression. Knockdown of TRPS1 resulted in perturbed mitosis, apoptosis, and reduced tumor growth. Integrated analysis of TRPS1 transcriptional targets, chromatin binding, and protein interactions revealed that TRPS1 is associated with the NuRD repressor complex. These findings uncover a transcriptional network that is essential for breast cancer cell survival and propagation. Witwicki et al. use a targeted shRNA screening strategy to identify transcriptional and epigenomic dependencies in poorly differentiated human cancers. TRPS1 is a lineage-specific transcription factor that is required for mitosis in breast cancer cells. TRPS1 is associated with the NuRD complex, and it regulates cell adhesion, cytoskeleton, and G2-M phase-related genes.