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

The erbB family of receptor tyrosine kinases, which consists of the epiderm al growth factor receptor (EGFr/erbB1), erbB2 (neu), erbB3 and erbB4, has b een 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 epide rmis with the bovine keratin 5 promoter. Overexpression of wild type rat er bB2 in the basal layer of epidermis led to alopecia, follicular hyperplasia and sebaceous gland enlargement as well as hyperplasia of the interfollicu lar epidermis. Spontaneous papillomas, some of which converted to squamous cell carcinomas, arose in homozygous erbB2 transgenic mice as early as 6 we eks of age with >90% incidence by 6 months. Analysis of several proliferati onl differentiation markers indicated that erbB2 overexpression led to epid ermal hyperproliferation and a possible delay in epidermal differentiation. Transgenic mice were also hypersensitive to the proliferative effects of t he skin tumor promoter, 12-0-tetradecanoylphorbol-13-acetate (TPA) and were more sensitive to two-stage carcinogenesis. Elevations in EGFr and erbB2 p rotein as well as erbB2:EGFr and erbB2:erbB3 heterodimers were observed in skin of the erbB2 transgenic mice. Phosphotyrosine levels of the EGFr, erbB 2 and erbB3 proteins were also elevated. These results indicate an importan t role for erbB2 signaling in epidermal growth, development and neoplasia.