@article{1552b09b574c44d184266dfc9e2ae017,
title = "TRPS1 Is a Lineage-Specific Transcriptional Dependency in Breast Cancer",
abstract = "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.",
keywords = "Lineage dependency, NuRD complex, TRPS1, breast cancer, mitosis, shRNA screen, transcriptional repressor",
author = "Witwicki, {Robert M.} and Ekram, {Muhammad B.} and Xintao Qiu and Michalina Janiszewska and Shaokun Shu and Mijung Kwon and Anne Trinh and Elizabeth Frias and Nadire Ramadan and Greg Hoffman and Kristine Yu and Yingtian Xie and Gregory McAllister and Rob McDonald and Javad Golji and Michael Schlabach and Antoine deWeck and Nicholas Keen and Chan, {Ho Man} and David Ruddy and Tomas Rejtar and Sosathya Sovath and Serena Silver and Sellers, {William R.} and Zainab Jagani and Hogarty, {Michael D.} and Charles Roberts and Myles Brown and Kimberly Stegmaier and Henry Long and Shivdasani, {Ramesh A.} and David Pellman and Kornelia Polyak",
note = "Funding Information: We thank members of our laboratories for their critical reading of this manuscript and useful discussions. We thank Patrick Reynolds and the Children{\textquoteright}s Oncology Group/Alex{\textquoteright}s Lemonade Stand Foundation (COG/ALSF) Childhood Cancer Repository ( www.CCcells.org ) for the neuroblastoma cell lines. This research was supported by the National Cancer Institute (NCI) R35 CA197623 (K.P.), K99 CA201606 (M.J.), and P01 CA080111 (K.P., M.B.), National Institute of Neurological Disorders and Stroke (NINDS) R01 NS088355 (K.S.), Susan G. Komen Foundation (S.S.), the Ludwig Center at Harvard (K.P. and M.B.), and the Novartis Institute for Biomedical Research (K.P., M.B., K.S., C.R., R.S.). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the NIH , and by the NCI , the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and NINDS . The data used for the analyses described in this manuscript were obtained from the GTEx Portal on December 12, 2017. Funding Information: We thank members of our laboratories for their critical reading of this manuscript and useful discussions. We thank Patrick Reynolds and the Children's Oncology Group/Alex's Lemonade Stand Foundation (COG/ALSF) Childhood Cancer Repository (www.CCcells.org) for the neuroblastoma cell lines. This research was supported by the National Cancer Institute (NCI) R35 CA197623 (K.P.), K99 CA201606 (M.J.), and P01 CA080111 (K.P., M.B.), National Institute of Neurological Disorders and Stroke (NINDS) R01 NS088355 (K.S.), Susan G. Komen Foundation (S.S.), the Ludwig Center at Harvard (K.P. and M.B.), and the Novartis Institute for Biomedical Research (K.P., M.B., K.S., C.R., R.S.). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the NIH, and by the NCI, the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on December 12, 2017. Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2018",
month = oct,
day = "30",
doi = "10.1016/j.celrep.2018.10.023",
language = "English",
volume = "25",
pages = "1255--1267.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}