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A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1

Oncogene volume 29, pages 2467–2476 (2010)Cite this article

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Abstract

The tumor suppressor gene hypermethylated in cancer 1 (HIC1), which encodes a transcriptional repressor, is epigenetically inactivated in various human cancers. In this study, we show that HIC1 is a direct transcriptional repressor of the gene encoding ephrin-A1, a cell surface ligand implicated in the pathogenesis of epithelial cancers. We also show that mouse embryos lacking both Hic1 alleles manifest developmental defects spatially associated with the misexpression of ephrin-A1, and that overexpression of ephrin-A1 is a feature of tumors arising in Hic1 heterozygous mice in which the remaining wild-type allele is epigenetically silenced. In breast cancer, we find that ephrin-A1 expression is common in vivo, but that in cell culture, expression of the EphA receptors is predominant. Restoration of HIC1 function in breast cancer cells leads to a reduction in tumor growth in vivo, an effect that can be partially rescued by co-overexpression of ephrin-A1. Interestingly, overexpression of ephrin-A1 in vitro triggers downregulation of EphA2 and EphA4 levels, resulting in an expression pattern similar to that seen in vivo. We conclude that Hic1 spatially restricts ephrin-A1 expression in development, and that upregulated expression of ephrin-A1 resulting from epigenetic silencing of HIC1 in cancer cells may be an important mechanism in epithelial malignancy.

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Acknowledgements

This work was supported by the National Cancer Institute Grant R01 CA43318 (SB Baylin) and an American Cancer Society Postdoctoral Fellowship (W Zhang). We thank Craig D Peacock, Leslie Meszler and Lillian Dasko-Vincent for technical assistance, Leander Van Neste for biostatistical support and Kathy Bender for the preparation and submission of this paper.

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Author notes

  1. W Zhang, X Zeng and K J Briggs: These authors contributed equally to this work.

Authors and Affiliations

  1. The Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    W Zhang, X Zeng, K J Briggs, R Beaty, B Simons, R-W Chiu Yen, M A Tyler, H-C Tsai, Y Ye, G S Gesell, J G Herman, S B Baylin & D N Watkins

  2. Graduate Training Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    X Zeng, K J Briggs & H-C Tsai

  3. Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia

    D N Watkins

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Correspondence to S B Baylin or D N Watkins.

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Zhang, W., Zeng, X., Briggs, K. et al. A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1. Oncogene 29, 2467–2476 (2010). https://doi.org/10.1038/onc.2010.12

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