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

Mol Carcinog. 1999 Jun;25(2):122-31. doi: 10.1002/(sici)1098-2744(199906)25:2<122::aid-mc7>3.0.co;2-8.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anthracenes / toxicity
  • Benzoyl Peroxide / toxicity
  • Carcinogens / toxicity*
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Mice
  • Mice, Transgenic
  • Okadaic Acid / toxicity
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction
  • Skin Neoplasms / chemically induced*
  • Tetradecanoylphorbol Acetate / toxicity
  • Transgenes


  • Anthracenes
  • Carcinogens
  • Okadaic Acid
  • chrysarobin
  • ErbB Receptors
  • Receptor, IGF Type 1
  • Tetradecanoylphorbol Acetate
  • Benzoyl Peroxide