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Enhancement of susceptibility to diverse skin tumor promoters by activation of the insulin‐like growth factor‐1 receptor in the epidermis of transgenic mice
Author(s) -
Wilker Erik,
Bol David,
Kiguchi Kaoru,
Rupp Tim,
Beltrán Linda,
DiGiovanni John
Publication year - 1999
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/(sici)1098-2744(199906)25:2<122::aid-mc7>3.0.co;2-8
Subject(s) - biology , epidermis (zoology) , transgene , genetically modified mouse , promoter , skin tumor , microbiology and biotechnology , receptor , cancer research , endocrinology , genetics , gene , anatomy , gene expression , carcinogenesis
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 promotion in mouse skin. HK1.IGF1 transgenic mice, which overexpress IGF‐1 in epidermis via the human keratin 1 promoter, were previously shown to be hypersensitive to skin tumor promotion by 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA). We examined these mice for their sensitivity to diverse classes of tumor‐promoting agents. HK1.IGF‐1 transgenic mice initiated with 7,12‐dimethylbenz[ a ]anthracene were more sensitive to treatment with a wide variety of tumor 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‐transgenic mice treated with the same compounds. Histological analyses of skin from HK1.IGF‐1 mice treated with various tumor promoters revealed that these mice were also more sensitive to the induction of epidermal hyperplasia and cell proliferation. Analysis of the IGF‐1 receptor (IGF‐1r) and epidermal growth factor (EGFr) in the epidermis of TPA‐treated HK1.IGF‐1 transgenic and non‐transgenic mice revealed that both receptors were activated (hyperphosphorylated on tyrosine residues), and the level of activation was higher in transgenic mice. The mechanism for the increased sensitivity of HK1.IGF‐1 mice to tumor promoters may involve cooperation between the IGF‐1r and EGFr signaling pathways. Our data suggest that IGF‐1r signaling may play an important role in the process of tumor promotion by diverse classes of tumor promoters. Mol. Carcinog. 25:122–131, 1999. © 1999 Wiley‐Liss, Inc.