NOTCH and EZH2 collaborate to repress PTEN expression in breast cancer

• DOI: 10.1038/s42003-021-01825-8
• Publication Date: 2021-03-09T11:03:14Z
• Authors: Kyrie Pappas; Tiphaine C. Martin; Andrew L. Wolfe; Christie B. Nguyen; Tao Su; Jian Jin; Hanina Hibshoosh; Ramon Parsons
• Keywords: 0301 basic medicine; Transcription, Genetic; QH301-705.5; PTEN Phosphohydrolase; Down-Regulation; Breast Neoplasms; Article; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Cell Line, Tumor; Mutation; Humans; Enhancer of Zeste Homolog 2 Protein; Female; Receptor, Notch2; Biology (General); Gene Fusion; Receptor, Notch1; Cell Proliferation

Abstract Downregulation of the PTEN tumor suppressor transcript is frequent in breast cancer and associates with poor prognosis triple-negative (TNBC) when comparing cancers to one another. Here we show that almost all cases, tumors adjacent normal ducts, expression decreased PRC2-associated methyltransferase EZH2 increased. We further find cases large cohorts, inversely correlates expression. Within highest expressing group, NOTCH alterations are frequent, also associate repression occurs through combined action ( NOTCH1 or NOTCH2 ) a subset cancers. In fact, harboring mutation fusion gene, drives EZH2, HES-1, HEY-1 repress transcription at promoter, which may contribute this subgroup. Restoration can be achieved an inhibitor (UNC1999), γ-secretase (Compound E), knockdown . These findings elucidate mechanism transcriptional induced by alterations, identifies actionable signaling pathways responsible for driving poor-prognosis