Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program

• DOI: 10.1038/s41467-018-04864-8
• Publication Date: 2018-06-25T11:53:49Z
• Authors: Alison Hirukawa; Harvey W. Smith; Dongmei Zuo; Catherine R. Dufour; Paul Savage; Nicholas Bertos; Radia M. Johnson; Tung Bui; Guillaume Bourque; Mark Basik; Vincent Giguère; Morag Park; William J. Muller
• Keywords: Epigenomics; Reprogramming; PRC2

Abstract Emerging evidence has illustrated the importance of epigenomic reprogramming in cancer, with altered post-translational modifications histones contributing to pathogenesis. However, contributions histone modifiers breast cancer progression are unclear, and how these processes vary between molecular subtypes yet be adequately addressed. Here we report that genetic or pharmacological targeting epigenetic modifier Ezh2 dramatically hinders metastatic behaviour both a mouse model patient-derived xenografts reflective Luminal B subtype. We further define subtype-specific mechanism whereby EZH2 maintains H3K27me3-mediated repression FOXC1 gene, thereby inactivating FOXC1-driven, anti-invasive transcriptional program. demonstrate higher is predictive favourable outcome specifically patients establish use methyltransferase inhibitors as viable strategy block metastasis where options for targeted therapy limited.