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Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors

Oncogene volume 23, pages 3972–3979 (2004)Cite this article

Abstract

E6/E7 oncogenes of high-risk human papilloma virus (HPV) subtypes are essential for the development of certain types of cancers. However, these oncogenes are insufficient to transform normal cells into an immortalized or malignant state. Mutant Ha-ras cooperates with E6/E7 of HPV subtype 16 in transformation of cells in vitro and may contribute to some HPV-associated cancers in humans. This study investigates whether HPV16 E6/E7 and v-Ha-ras synergize in vivo. FVB/n mice transgenic for v-Ha-ras gene (R+) were crossed with transgenic C57BL/6 mice that harbor E6/E7 of HPV16 (E+). Beginning at about 3 months of age, the bitransgenic E+R+(C57BL/6 × FVB/n) F1 mice developed mouth, eye and ear tumors. By 6 months, the prevalence of these types of mouth, eye and ear tumors was 100, 71 and 79% respectively in the E+R+ mice. Most tumors grew progressively until the mice had to be killed. The median times for the appearance of the first mouth, eye and ear tumor were 3.6, 4.3 and 4.2 months, respectively. For the two singly transgenic groups of mice, the prevalence of mouth, eye and ear tumors was 0, 0 and 6% (E−R+) and 0, 0 and 0% (E+R−), respectively, and the median time to first tumor was greater than 12 months for singly transgenic mice (E−R+, E+R−). Thus, a remarkable synergy occurred between the v-Ha-ras and HPV16 E6/E7 oncogenes in the development of primary tumors in mice.

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Acknowledgements

We thank Donald A Rowley, Michael T Spiotto and Michele Carbone for their critical suggestions during the course of the study and for reviewing the manuscript. We also thank Gordon Bowie for excellent photographical work, Christine Langan and Keith Voogd for excellent technical support and Ruthie Cornelius for help with preparing the manuscript. This work was supported by National Institute of Health Grants P01-CA97296, R01-CA22677 and R01-CA37516, and a grant by a pre-Clinical grant from the Cancer Research Institute.

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Authors and Affiliations

  1. Department of Pathology, The University of Chicago, MC 3008, 5841 S. Maryland Ave, Chicago, 60637, IL, USA

    Karin Schreiber, Theodore Karrison, Gabriele Beck-Engeser, Heather Jensen, Stephen C Meredith & Hans Schreiber

  2. Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, 27709, NC, USA

    Ronald E Cannon & Raymond W Tennant

  3. Department of Health Studies, The University of Chicago, Chicago, 60637, IL, USA

    Dezheng Huo & Thomas Krausz

  4. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, 90089, CA, USA

    W Martin Kast

  5. Department of Immunology, Mayo Clinic, Rochester, 55905, MN, USA

    Lieping Chen

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  1. Karin Schreiber
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Correspondence to Hans Schreiber.

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Schreiber, K., Cannon, R., Karrison, T. et al. Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors. Oncogene 23, 3972–3979 (2004). https://doi.org/10.1038/sj.onc.1207507

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