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A positive role of DBC1 in PEA3-mediated progression of estrogen receptor-negative breast cancer

Oncogene volume 34, pages 4500–4508 (2015)Cite this article

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Abstract

Deleted in Breast Cancer 1 (DBC1), a negative regulator of deacetylase SIRT1, has been shown to act as an estrogen receptor α (ER) coactivator that has a key role in ER transcription complex assembly and estrogen-dependent breast cancer cell proliferation. However, little is known about its physiological role and mechanism of action in ER-negative breast cancer cells. Here we report that DBC1 functions as a coactivator for the oncogenic ETS transcription factor PEA3 to promote ER-negative breast cancer progression. DBC1 is required for the expression of PEA3 target genes and for recruitment of PEA3 and RNA polymerase II to PEA3 target promoters. We also demonstrated that acetylation of PEA3 stimulates its DNA binding and association with DBC1 by disrupting the intramolecular interaction of PEA3. The molecular mechanism underlying DBC1 function in PEA3-mediated transcription involves inhibition of SIRT1 interaction with PEA3 and of SIRT1-mediated deacetylation of PEA3. Moreover, DBC1 depletion inhibited the tumorigenic properties of ER-negative breast cancer cells in vitro and in vivo. Importantly, increased DBC1 expression correlated with shorter relapse-free survival of ER-negative breast cancer patients. Our results firmly established DBC1 as a critical coactivator of PEA3 and as a key player in PEA3-mediated breast cancer progression.

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Acknowledgements

We thank Jason W Chin (MRC Laboratory for Molecular Biology, Cambridge, UK) for providing vectors and Yoon-La Choi (Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea) for providing the tissue microarray slides of primary invasive breast carcinoma specimens. This work was supported by Samsung Biomedical Research Institute (SBRI) grant (SMX1132501) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2013R1A1A2059697) to JHK.

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  1. H J Kim and S-H Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea

    H J Kim, S-H Kim, E J Yu, W-Y Seo & J H Kim

  2. Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea

    H J Kim, E J Yu, W-Y Seo & J H Kim

  3. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    S-H Kim

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Correspondence to J H Kim.

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Kim, H., Kim, SH., Yu, E. et al. A positive role of DBC1 in PEA3-mediated progression of estrogen receptor-negative breast cancer. Oncogene 34, 4500–4508 (2015). https://doi.org/10.1038/onc.2014.381

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