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

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 and William J. Muller ()
Additional contact information
Alison Hirukawa: McGill University
Harvey W. Smith: McGill University
Dongmei Zuo: McGill University
Catherine R. Dufour: McGill University
Paul Savage: McGill University
Nicholas Bertos: McGill University
Radia M. Johnson: McGill University
Tung Bui: McGill University
Guillaume Bourque: Génome Québec Innovation Centre
Mark Basik: Jewish General Hospital
Vincent Giguère: McGill University
Morag Park: McGill University
William J. Muller: McGill University

Nature Communications, 2018, vol. 9, issue 1, 1-15

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

Date: 2018
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DOI: 10.1038/s41467-018-04864-8

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