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. Oncogene (2000) 19, 4243 - 4254
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Carcinogens / toxicity
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Carcinoma, Squamous Cell / chemically induced
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Carcinoma, Squamous Cell / genetics*
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Carcinoma, Squamous Cell / pathology
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Cattle
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Cell Differentiation
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Cell Division
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Cell Transformation, Neoplastic / genetics*
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Cocarcinogenesis
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Dimerization
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Disease Progression
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Epidermis / drug effects
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Epidermis / metabolism*
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Epidermis / pathology
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ErbB Receptors / chemistry
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ErbB Receptors / genetics
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Female
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Gene Expression Regulation*
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Gene Expression Regulation, Neoplastic
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Genes, Synthetic
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Genes, erbB-2*
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Genes, ras
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Hyperplasia
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Keratins / genetics
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Male
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Mice
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Mice, Inbred ICR
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Mice, Transgenic
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / genetics
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Papilloma / chemically induced
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Papilloma / genetics*
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Papilloma / pathology
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Phosphorylation
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Promoter Regions, Genetic
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Protein Processing, Post-Translational
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Rats
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Receptor, ErbB-2 / biosynthesis
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Receptor, ErbB-2 / chemistry
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Receptor, ErbB-2 / physiology*
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Receptor, ErbB-3 / metabolism
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / physiology
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Signal Transduction
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Skin Neoplasms / chemically induced
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Skin Neoplasms / etiology*
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Skin Neoplasms / pathology
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Tetradecanoylphorbol Acetate / toxicity
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Transgenes*
Substances
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Carcinogens
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Neoplasm Proteins
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Recombinant Fusion Proteins
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Keratins
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ErbB Receptors
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Receptor, ErbB-2
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Receptor, ErbB-3
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Tetradecanoylphorbol Acetate