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MEK–ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes

Oncogene volume 30, pages 4118–4128 (2011)Cite this article

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Abstract

EZH2 overexpression occurs in various malignancies and is associated with a poor outcome. We have so far demonstrated that EZH2 downregulates the important genes such as E-cadherin and RUNX3 by increasing histone H3K27 trimethylation. However, the mechanism of EZH2 overexpression in various cancer cells remains unclear. In this study we carried out a promoter analysis of the EZH2 gene and investigated whether a survival signal that is upregulated in cancer cells is related to overexpression at the transcription level. We also explored the clinical relevance of the signaling pathway that leads to EZH2 overexpression in breast cancer and demonstrated that MEK–ERK1/2–Elk–1 pathway leads to EZH2 overexpression. The triple-negative and ERBB2-overexpressing subtypes of breast cancer are known to contain more rapidly proliferating breast cancer cells. The signaling pathway connected to EZH2 overexpression was associated with both aggressive subtypes of breast cancer. We show the significance that overexpression of histone modifier protein EZH2 in cancer cells and our study could pave the way for EZH2 inhibition to become an efficient treatment for more aggressive breast cancers.

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Acknowledgements

We wish to acknowledge the assistance of Ms Hiroko Hashimoto for cell culture support and the assistance of Mr Shinya Yanagi for making paraffin-embedded thin sections for immunohistochemistry. The research described in this report has been funded by a grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan (21590453), to SF. Individual contributions of each author; Study concept and design; SF, AO, Acquisition of data; SF, KT, Analysis and interpretation of data; SF, KT, NW, Drafting the manuscript; SF, Critical revision of the manuscript for important intellectual content; SF, KI, YI, AO. Statistical analysis; SF, KT, NW Obtained funding; SF, Material support; NW, KI, YI, CY, Study supervision; SF.

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Authors and Affiliations

  1. Pathology Division, Research Center for Innovative Oncology, National Cancer Center at Kashiwa, Kashiwa, Chiba, Japan

    S Fujii, K Tokita, C Yamauchi & A Ochiai

  2. Breast Surgery Division, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    N Wada

  3. Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

    K Ito

  4. Cancer Science Institute of Singapore, Proteos, Singapore

    Y Ito

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  1. S Fujii
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Correspondence to A Ochiai.

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Fujii, S., Tokita, K., Wada, N. et al. MEK–ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes. Oncogene 30, 4118–4128 (2011). https://doi.org/10.1038/onc.2011.118

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