Abstract 1700: Interplay of pioneer and chromatin remodeling factors: New insights into breast cancer mechanisms

Abstract

Abstract Eukaryotic cells utilize chromatin to package their genomic DNA, which can hinder transcription factor binding and gene activation. Pioneer factors, which can activate silent chromatin by binding to nucleosomes in closed (inactive) chromatin regions, thereby increasing chromatin accessibility, are essential in multiple developmental pathways. Their misregulation has been linked to various human diseases, including cancer. Yet, the involvement of pioneer factor mutations in tumorigenesis and tumor progression remains largely unexplored. GATA3 is one of the most frequently mutated genes in breast cancer. We and other groups found that a subset of GATA3 mutations promote tumor growth by redirecting luminal transcriptional network governed by Estrogen Receptor alpha (ER-alpha), FOXA1, and GATA3. Our genomics data also suggested that GATA3 requires multiple co-factors to maintain and establish active enhancers. Through IP-mass spectrometry, we identified several chromatin remodeling factors as potential GATA3 binding partners, with CHD4 being particularly notable. Our genomic data, including ChIP-seq, ATAC-seq, and RNA-seq, suggest that during GATA3-induced mesenchymal-to-epithelial transition (MET), CHD4 plays a critical role in maintaining closed chromatin structure, particularly at enhancer regions. Depletion of CHD4 results in the activation of chromatin and genes that are not essential for successful MET. Furthermore, we observed functional interactions between GATA3 and PARP1 in both luminal and basal breast cancer cells, with notable changes in GATA3 mutant cells. Through these studies, we aim to uncover epigenetic vulnerabilities in GATA3-altered breast cancer cells, ultimately contributing to the development of new breast cancer treatments. Citation Format: Motoki Takaku, Mikhal Cooper, Mika Saotome. Interplay of pioneer and chromatin remodeling factors: New insights into breast cancer mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1700.