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

Author

Listed:
  • Alison Hirukawa

    (McGill University
    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
    McGill University)

  • Guillaume Bourque

    (Génome Québec Innovation Centre
    McGill University)

  • Mark Basik

    (Jewish General Hospital
    McGill University)

  • Vincent Giguère

    (McGill University
    McGill University
    McGill University)

  • Morag Park

    (McGill University
    McGill University
    McGill University)

  • William J. Muller

    (McGill University
    McGill University
    McGill University)

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.

Suggested Citation

  • 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 & Wi, 2018. "Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04864-8
    DOI: 10.1038/s41467-018-04864-8
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    Cited by:

    1. Lin Zhang & Jingkun Qu & Yutao Qi & Yimin Duan & Yu-Wen Huang & Zhifen Zhou & Ping Li & Jun Yao & Beibei Huang & Shuxing Zhang & Dihua Yu, 2022. "EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Yael Aylon & Noa Furth & Giuseppe Mallel & Gilgi Friedlander & Nishanth Belugali Nataraj & Meng Dong & Ori Hassin & Rawan Zoabi & Benjamin Cohen & Vanessa Drendel & Tomer Meir Salame & Saptaparna Mukh, 2022. "Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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