Targeted overexpression of transforming growth factor alpha in the epidermis of transgenic mice elicits hyperplasia, hyperkeratosis, and spontaneous, squamous papillomas.

To assess the effects of transforming growth factor alpha (TGF-alpha) on mammalian skin in vivo, we have targeted its expression to the epidermis of transgenic mice using a vector based on the human K1 (HK1) gene. Neonatal mice expressing the HK1.TGF-alpha transgene were often smaller than normal littermates and had precocious eyelid opening and wrinkled, scaly skin with diffuse alopecia. Juvenile transgenic mouse epidermis was uniformly hyperkeratotic, but this pattern was generally less pronounced in adult transgenic mice unless they expressed high levels of the HK1.TGF-alpha transgene. Spontaneous, squamous papillomas occurred at sites of wounding in adult mice expressing high levels of HK1.TGF-alpha; however, most were prone to regression. Immunoreactive TGF-alpha was 2-6 times higher in the epidermis of these HK1.TGF-alpha lines. Immunoreactive epidermal growth factor receptor had a normal pattern of expression in nonphenotypic adult epidermis, but a marked reduction in the receptor population was detected in hyperplastic newborn epidermis and phenotypic adult epidermis. Autoradiographic localization of 125I-epidermal growth factor showed a similar pattern of distribution, suggesting that the sites of increased TGF-alpha expression induced epidermal growth factor receptor down-regulation. These data demonstrate the in vivo effect of deregulated TGF-alpha expression on epidermal proliferation and differentiation and suggest a potential role for TGF-alpha in carcinogenesis and other hyperproliferative epidermal disorders.