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Tumor suppressor ARF inhibits HER-2/neu-mediated oncogenic growth

Oncogene volume 23, pages 7132–7143 (2004)Cite this article

Abstract

HER2/neu, a receptor tyrosine kinase oncogene, promotes mitogenic growth and antiapoptotic activity in cancer cells. Strong expression of HER2/neu in cancers has been associated with poor prognosis. Alternative reading frame protein (ARF), a tumor suppressor protein encoded by a gene located in the Ink4a/ARF gene locus, is frequently inactivated in human cancers. Little is known about the tumor suppressor role of ARF in HER2/neu-overexpressing cancers. Here, we applied the ARF gene as a tumor-suppressive agent for HER2/neu-overexpressing cells under the control of a tetracycline (tet)-regulated gene expression system. We found that ARF antagonized protein kinase B (PKB)/Akt-mediated p27Kip1 phosphorylation and increased p27 stability in HER2/neu-overexpressing cells. ARF expression also led to decreased levels of Cul1 and Skp2, two proteins involved in p27 degradation. We also found that ARF caused apoptosis in HER2/neu-overexpressing cells, and sensitized cells to apoptosis induced by the chemotherapeutic agents taxol and 2-methoxyestradiol. Most significantly for clinical application, we found that ARF inhibited HER2/neu-mediated cell growth, transformation, and tumorigenesis. These findings indicate that modulation of ARF activity may be a useful therapeutic intervention in HER2-overexpressing cancers.

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Acknowledgements

We thank Drs Hung, Pagano, and Pestell for valuable reagents. This work was supported by a grant from the NIH RO1CA (089266) and by the Susan G Komen Breast Cancer Foundation. M-H Lee is a recipient of the Flemin and Davenport research award and the Susan G Koman Breast Cancer Foundation research award.

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Yujiang Zhang, Heng-Yin Yang, Xiao-Chun Zhang, Huiling Yang, Mayli Tsai & Mong-Hong Lee

  2. Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA

    Mong-Hong Lee

  3. Program in Genes & Development, The University of Texas Graduate School of Biomedical Sciences at Houston, TX, USA

    Mong-Hong Lee

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  1. Yujiang Zhang
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Correspondence to Mong-Hong Lee.

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Zhang, Y., Yang, HY., Zhang, XC. et al. Tumor suppressor ARF inhibits HER-2/neu-mediated oncogenic growth. Oncogene 23, 7132–7143 (2004). https://doi.org/10.1038/sj.onc.1207918

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