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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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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. |
format | Online Article Text |
id | pubmed-6026192 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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