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Constitutive expression of erbB2 in epidermis of transgenic mice results in epidermal hyperproliferation and spontaneous skin tumor development

Oncogene volume 19, pages 4243–4254 (2000)Cite this article

Abstract

The erbB family of receptor tyrosine kinases, which consists of the epidermal growth factor receptor (EGFr/erbB1), erbB2 (neu), erbB3 and erbB4, has been shown to be important for both normal development as well as neoplasia. The expression of rat erbB2 was targeted to the basal layer of mouse epidermis with the bovine keratin 5 promoter. Overexpression of wild type rat erbB2 in the basal layer of epidermis led to alopecia, follicular hyperplasia and sebaceous gland enlargement as well as hyperplasia of the interfollicular epidermis. Spontaneous papillomas, some of which converted to squamous cell carcinomas, arose in homozygous erbB2 transgenic mice as early as 6 weeks of age with >90% incidence by 6 months. Analysis of several proliferation/differentiation markers indicated that erbB2 overexpression led to epidermal hyperproliferation and a possible delay in epidermal differentiation. Transgenic mice were also hypersensitive to the proliferative effects of the skin tumor promoter, 12-0-tetradecanoylphorbol-13-acetate (TPA) and were more sensitive to two-stage carcinogenesis. Elevations in EGFr and erbB2 protein as well as erbB2:EGFr and erbB2:erbB3 heterodimers were observed in skin of the erbB2 transgenic mice. Phosphotyrosine levels of the EGFr, erbB2 and erbB3 proteins were also elevated. These results indicate an important role for erbB2 signaling in epidermal growth, development and neoplasia.

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Acknowledgements

The authors wish to acknowledge the assistance of Carrie McKinley in the preparation of this manuscript. Research supported by NIH grants CA76520 (J DiGiovanni), MDACC Cancer Center Support Grant CA16672, and NIEHS Center Grant ES07784.

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Author notes

  1. David Bol

    Present address: Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, 08543, NJ, USA

Authors and Affiliations

  1. Department of Carcinogenesis, Science Park-Research Division, The University of Texas, MD Anderson Cancer Center, PO Box 389, Smithville, Texas, 78957, TX, USA

    Kaoru Kiguchi, David Bol, Steve Carbajal, Linda Beltrán, Samantha Moats, Keith Chan & John DiGiovanni

  2. Department of Cell and Molecular Biology, Ciemat Instituto, Av. Complutense 22, Madrid, 28040, Spain

    José Jorcano

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Kiguchi, K., Bol, D., Carbajal, S. et al. Constitutive expression of erbB2 in epidermis of transgenic mice results in epidermal hyperproliferation and spontaneous skin tumor development. Oncogene 19, 4243–4254 (2000). https://doi.org/10.1038/sj.onc.1203778

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