Enhancement of susceptibility to diverse skin tumor promoters by activation of the insulin-like growth factor-1 receptor in the epidermis of transgenic mice

Insulin-like growth factor-1 (IGF-1) and its receptor are believed to play an important role in mitogenesis and neoplastic transformation. The purpose of this study was to further examine the role of IGF-1 during tumor promot ion in mouse skin. HK1.IGF1 transgenic mice, which overexpress IGF-1 in epi dermis via the human keratin 1 promoter, were previously shown to be hypers ensitive to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (T PA). We examined these mice for their sensitivity to diverse classes of tum or-promoting agents. HK1.IGF-1 transgenic mice initiated with 7,12-dimethyl benz[a]anthracene were more sensitive to treatment with a wide variety of t umor promoters, including chrysarobin, okadaic acid, and benzoyl peroxide, which resulted in more rapid development of tumors and a dramatic increase in the number of tumors per mouse compared with corresponding non-transgeni c mice treated with the same compounds. Histological analyses of skin from HK1.IGF-1 mice treated with various tumor promoters revealed that these mic e were also more sensitive to the induction of epidermal hyperplasia and ce ll proliferation. Analysis of the IGF-1 receptor (IGF-1r) and epidermal gro wth factor (ECFr) in the epidermis of TPA-treated HK1.IGF-1 transgenic and non-transgenic mice revealed that both receptors were activated (hyperphosp horylated on tyrosine residues), and the level of activation was higher in transgenic mice. The mechanism for the increased sensitivity of HK1.IGF-1 m ice to tumor promoters may involve cooperation between the ICF-1r and EGFr signaling pathways. Our data suggest that IGF-1r signaling may play an impo rtant role in the process of tumor promotion by diverse classes of tumor pr omoters. (C) 1999 Wiley-Liss, Inc.