2. Academic Validation
  3. Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program

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

  • Nat Commun. 2018 Jun 29;9(1):2547. doi: 10.1038/s41467-018-04864-8.
Alison Hirukawa 1 2,  Harvey W Smith 1,  Dongmei Zuo 1,  Catherine R Dufour 1,  Paul Savage 1,  Nicholas Bertos 1,  Radia M Johnson 1,  Tung Bui 1 2,  Guillaume Bourque 3 4,  Mark Basik 5 6,  Vincent Giguère 1 2 6,  Morag Park 1 2 6,  William J Muller 7 8 9
Affiliations

Affiliations

  • 1 Goodman Cancer Research Centre, McGill University, Montréal, QC, H3A 1A3, Canada.
  • 2 Department of Biochemistry, McGill University, Montréal, QC, H3G 1Y6, Canada.
  • 3 McGill University, Génome Québec Innovation Centre, Montréal, QC, H3A 0G1, Canada.
  • 4 Department of Human Genetics, McGill University, Montréal, QC, H3A 1A3, Canada.
  • 5 Department of Surgery and Oncology, Jewish General Hospital, Montréal, QC, H3T 1E2, Canada.
  • 6 Departments of Medicine and Oncology, McGill University, Montréal, QC, H3G 1Y6, Canada.
  • 7 Goodman Cancer Research Centre, McGill University, Montréal, QC, H3A 1A3, Canada. william.muller@mcgill.ca.
  • 8 Department of Biochemistry, McGill University, Montréal, QC, H3G 1Y6, Canada. william.muller@mcgill.ca.
  • 9 Departments of Medicine and Oncology, McGill University, Montréal, QC, H3G 1Y6, Canada. william.muller@mcgill.ca.
PMID: 29959321 DOI: 10.1038/s41467-018-04864-8
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.

Figures
Products