Abstract ES13-1: Targeting EZH2 functions

Abstract

Abstract Anaplasia, or loss of mature specialized features, is a characteristic of malignant cells. Thus, it is not surprising that deregulation of proteins that govern cell type identity may lead to cancer. EZH2, a Polycomb group protein which regulates transcriptional memory in normal cells through H3K27 trimethylation, is overexpressed in breast cancer compared to normal breast, and is a tissue-based biomarker of survival in patients with breast cancer. EZH2 enhances breast cancer initiation and progression, making it a desirable therapeutic target with several inhibitors already in clinical trials. While the main mechanism of EZH2 oncogenic function has been ascribed to trimethylation of H3K27, mounting evidence supports that EZH2 also functions through non-canonical H3K27me3-independent mechanisms, especially in triple negative breast carcinomas (TNBC). These include transcriptional activation through direct binding to the NOTCH1 promoter to regulate cancer stem cells, and EZH2 phosphorylation at specific sites to either reduce affinity for histone H3 and/or increase binding to nonhistone proteins to promote metastasis. This body of work highlights the importance of blocking EZH2 H3K27me3-dependent as well as non-canonical functions in TNBC to improve outcomes. In this Educational Session, I will discuss current insights into EZH2 oncogenic mechanisms in TNBC including metaplastic carcinomas, an aggressive and chemoresistant TNBC subtype. We will also discuss how the discovery of novel EZH2 mechanisms may set the stage for the development of previously unconsidered therapeutic opportunities. Citation Format: CG Kleer. Targeting EZH2 functions [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES13-1.