OVEREXPRESSION OF INSULIN-LIKE GROWTH-FACTOR-I INDUCES HYPERPLASIA, DERMAL ABNORMALITIES, AND SPONTANEOUS TUMOR-FORMATION IN TRANSGENIC MICE

Transgenic animals were developed to assess the role of insulin-like g rowth factor 1 (IGF-1) in skin growth, differentiation and organizatio n, as well as its importance in tumor formation. Expression of a human IGF-1 cDNA was targeted to the interfollicular epidermis of transgeni c mice using a human keratin 1 promoter construct (HK1). Transgenic an imals (HK1.IGF-1 mice) could be identified at birth by early ear unfol ding and excessive ear and skin growth compared to nontransgenic litte rmates. Further examination of the skin from these mice showed epiderm al hyperplasia and hyperkeratosis, marked thickening of the dermis and hypodermis, and early hair follicle generation in newborns. The sever ity of this phenotype correlated with transgene expression both of whi ch subsided,vith age. Adult HK1.IGF-1 mice developed spontaneous tumor s following treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) alone and exhibited an exaggerated epidermal proliferative response fo llowing treatment with the tumor promoter compared to non transgenic l ittermates. Additionally, HK1.IGF-1 transgenic mice developed papillom as faster and in markedly greater numbers compared to non-transgenic l ittermates in standard initiation-promotion experiments. The data pres ented suggest an important role for IGF-I in the process of multistage carcinogenesis in mouse skin.