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Cyclin D1 is essential for neoplastic transformation induced by both E6/E7 and E6/E7/ErbB-2 cooperation in normal cells

Oncogene volume 23, pages 5252–5256 (2004)Cite this article

Abstract

More than 25% of head and neck squamous cell carcinomas (HNSCC) and 99% of cervical cancers (CxCa) are positive for high-risk human papillomaviruses (HPVs). Furthermore, the type I tyrosine kinase receptor ErbB-2 is overexpressed in at least 30% of HNSCC and CxCa. Recently, we demonstrated that E6/E7 of HPV type 16 cooperate with ErbB-2 to induce cell transformation of human normal oral epithelial (NOE) cells. This is accompanied by overexpression of cyclin D1 in NOE cells. To determine the role of cyclin D1 in E6/E7/ErbB-2 cooperation, we examined the independent effects of E6/E7 and ErbB-2, and the combined effect of E6/E7 and ErbB-2 in mouse normal embryonic fibroblast (NEF), wild type (wt), and knockout cyclin D1 (D1−/−) cells. We report that NEF-wt cells transduced with E6/E7 alone and E6/E7/ErbB-2 together form small and large tumors in nude mice, respectively, as well as different sized colonies in soft agar; whereas ErbB-2 alone elicits neither tumor formation in vivo nor colony formation in soft agar. More importantly, E6/E7, ErbB-2 and E6/E7/ErbB-2 together all fail to induce neoplastic transformation of cyclin D1−/− cells in vivo and in vitro. Furthermore, using antisense cyclin D1 we completely inhibited tumor and colony formation of NEF-wt-E6/E7 and wt-E6/E7-ErbB-2 as well as human NOE-E6/E7-ErbB-2-transformed cells. These analyses reveal that cyclin D1 is the downstream target of the neoplastic transformation induced by E6/E7 or E6/E7/ErbB-2 cooperation in normal cells. Our data suggest that anti-cyclin D1 therapy may be highly specific in the treatment of all human cancers expressing high-risk HPVs or HPVs/ErbB-2.

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Acknowledgements

We are grateful to Drs D Hamilton and N Eliopoulos for the critical reading of the manuscript. We also thank T Wang and A Hosein for their technical assistance. This work is supported by the Cancer Research Society Inc. (A-EA, WDF), le Fonds de la Recherche en Santé du Québec (FRSQ- Réseau du Cancer) (WDF, GB, A-EA), the National Cancer Institute of Canada Grant # 010254 (WDF) and the Canadian Genetic Diseases Network Summer Studentship (AW).

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Author notes

  1. Ala-Eddin Al Moustafa: This work is dedicated to the memory of my beloved wife Naima Bachnou.

Authors and Affiliations

  1. Program in Cancer Genetics, McGill University, Montreal, Quebec, Canada

    Ala-Eddin Al Moustafa, William D Foulkes, Annick Wong & Houda Jallal

  2. Departments of Oncology, The Centre for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research of the Sir Mortimer B Davis-Jewish General Hospital, Medicine, Pathology, Pharmacology and Therapeutics, McGill University, Montreal, H3T 1E2, Quebec, Canada

    Ala-Eddin Al Moustafa, William D Foulkes, Annick Wong, Houda Jallal, Gerald Batist & Moulay A Alaoui-Jamali

  3. Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada

    William D Foulkes

  4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Qunyan Yu & Piotr Sicinski

  5. Department of Pathology, Harvard Medical School, Boston, MA, USA

    Qunyan Yu & Piotr Sicinski

  6. The Wistar Institute, Philadelphia, Pennsylvania

    Meenhard Herlyn

  7. Fox Chase Cancer Centre, Philadelphia, PA, USA

    Meenhard Herlyn

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  1. Ala-Eddin Al Moustafa
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Correspondence to Ala-Eddin Al Moustafa.

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Al Moustafa, AE., Foulkes, W., Wong, A. et al. Cyclin D1 is essential for neoplastic transformation induced by both E6/E7 and E6/E7/ErbB-2 cooperation in normal cells. Oncogene 23, 5252–5256 (2004). https://doi.org/10.1038/sj.onc.1207679

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