Constitutive expression of insulin-like growth factor-1 in epidermal basalcells of transgenic mice leads to spontaneous tumor promotion

Transgenic mice overexpressing insulin-like growth factor-1 (IGF-1) in the basal layer of skin epidermis were generated using the bovine keratin 5 pro moter (BK5), Neonatal transgenic mice were slightly smaller at birth and ex hibited early ear unfolding, wrinkled and thickened skin, and slightly enla rged ears compared with nontransgenic littermates. Morphological evaluation of the skin revealed that persistent overexpression of IGF-1 in the basal laver of the epidermis resulted in epidermal hyperplasia, hyperkeratosis, a nd an increased labeling index that persisted in adult mice, Phenotypic cha nges observed in skin were associated with transgene expression in the basa l layer of the epidermis and activation of the IGF-1 receptor, Squamous pap illomas (some of which converted to carcinomas) developed in a significant proportion (similar to 50%) of older BK5.IGF-1 mice. Treatment of BK5.IGF-1 transgenic mice with multiple topical applications of the phorbol ester, 1 2-O-tetradecanoylphorbol-13-acetate, in the absence of tumor initiation led to the development of additional skin papillomas. Furthermore, treatment o f BK5.IGF-1 transgenic mice with an initiating dose of 7,12-dimethylbenz[a] anthracene only led to the formation of additional papillomas in the absenc e of promotion. In two-stage carcinogenesis experiments, BK5.IGF-1 transgen ic mice developed 7-fold more papillomas than nontransgenic littermates. Ph osphatidylinositol-3-kinase and protein kinase B (Akt) activities mere elev ated (3-4-fold), and mitogen-activated protein kinase activity vias elevate d similar to 1.7-fold in the epidermis of transgenic mice compared with non transgenic mice. In addition, UV light-induced epidermal apoptosis was sign ificantly suppressed in BK5.IGF-1 transgenic mice. These data suggest that persistent activation of IGF-1 receptor signaling pathways in basal epithel ial cells leads to spontaneous tumor promotion and that up-regulation of bo th mitogenic and cell survival signaling pathways may play an important rol e in the action of IGF-1 in this model system.