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

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 betwe...

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Autores principales: Hirukawa, Alison, Smith, Harvey W., Zuo, Dongmei, Dufour, Catherine R., Savage, Paul, Bertos, Nicholas, Johnson, Radia M., Bui, Tung, Bourque, Guillaume, Basik, Mark, Giguère, Vincent, Park, Morag, Muller, William J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026192/
https://www.ncbi.nlm.nih.gov/pubmed/29959321
http://dx.doi.org/10.1038/s41467-018-04864-8
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author Hirukawa, Alison
Smith, Harvey W.
Zuo, Dongmei
Dufour, Catherine R.
Savage, Paul
Bertos, Nicholas
Johnson, Radia M.
Bui, Tung
Bourque, Guillaume
Basik, Mark
Giguère, Vincent
Park, Morag
Muller, William J.
author_facet Hirukawa, Alison
Smith, Harvey W.
Zuo, Dongmei
Dufour, Catherine R.
Savage, Paul
Bertos, Nicholas
Johnson, Radia M.
Bui, Tung
Bourque, Guillaume
Basik, Mark
Giguère, Vincent
Park, Morag
Muller, William J.
author_sort Hirukawa, Alison
collection PubMed
description 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.
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spelling pubmed-60261922018-07-02 Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program Hirukawa, Alison Smith, Harvey W. Zuo, Dongmei Dufour, Catherine R. Savage, Paul Bertos, Nicholas Johnson, Radia M. Bui, Tung Bourque, Guillaume Basik, Mark Giguère, Vincent Park, Morag Muller, William J. Nat Commun Article 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. Nature Publishing Group UK 2018-06-29 /pmc/articles/PMC6026192/ /pubmed/29959321 http://dx.doi.org/10.1038/s41467-018-04864-8 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hirukawa, Alison
Smith, Harvey W.
Zuo, Dongmei
Dufour, Catherine R.
Savage, Paul
Bertos, Nicholas
Johnson, Radia M.
Bui, Tung
Bourque, Guillaume
Basik, Mark
Giguère, Vincent
Park, Morag
Muller, William J.
Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program
title Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program
title_full Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program
title_fullStr Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program
title_full_unstemmed Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program
title_short Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program
title_sort targeting ezh2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026192/
https://www.ncbi.nlm.nih.gov/pubmed/29959321
http://dx.doi.org/10.1038/s41467-018-04864-8
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