Developmental reprogramming of IGF signaling and susceptibility to endometrial hyperplasia in the rat

Lab Invest. 2008 Jun;88(6):615-26. doi: 10.1038/labinvest.2008.29. Epub 2008 Apr 21.


In rodents, a brief neonatal exposure of the developing reproductive tract to the xenoestrogen, diethylstilbestrol (DES) reprograms developing tissues to increase susceptibility to tumorigenesis in adult animals, including uterine adenocarcinoma. Progression from a normal endometrium to carcinoma occurs via the intermediate stage of endometrial hyperplasia. We previously reported that endometrial hyperplasia in postmenopausal women is linked to abnormal insulin-like growth factor-I (IGF-I) signaling. To identify early events involved in the development of hyperplasia in the endometrium, we examined expression and activation of IGF-I pathway components in endometrium of rats exposed to DES. By 5 months of age, 36/60 (60%) of rats exposed to DES on days 3-5 after birth developed endometrial hyperplasia compared to 0% of vehicle-treated controls. Consistent with activation of a mitogenic signaling pathway, Ki67-positive cells increased in DES-exposed endometrium despite compromised ovarian function and hypoestrogenic milieu characteristic of DES-exposed animals. The endometrium of DES-exposed rats overexpressed IGF-II and insulin receptor substrate-1 (IRS-1) and exhibited elevated Akt expression and activation (as judged by phosphorylation) and mTOR signaling (phosphorylation of S6) compared to vehicle-treated endometrium. In contrast to vehicle-treated endometrium, in which negative feedback to IRS-1 was observed (phosphorylation of S636/639), negative feedback to IRS-1 was absent in DES-exposed endometrium. These data support a central role for IGF-I signaling in the development of both human and rodent endometrial hyperplasia. Furthermore, both global activation of IGF-IR signaling and abrogation of negative feedback to IRS-1 appear to be reprogrammed by DES in endometrial hyperplasia, implicating for the first time loss of negative feedback to IRS-1 in development of a preneoplastic lesion.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Animals, Newborn
  • Carcinogens
  • Diethylstilbestrol
  • Endometrial Hyperplasia / chemically induced*
  • Endometrial Hyperplasia / pathology
  • Female
  • Genetic Predisposition to Disease*
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / metabolism*
  • Insulin-Like Growth Factor II / metabolism
  • Ki-67 Antigen / drug effects
  • Ki-67 Antigen / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Neoplasm / analysis
  • RNA, Neoplasm / isolation & purification
  • Rats
  • Rats, Mutant Strains
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction*
  • Time Factors


  • Adaptor Proteins, Signal Transducing
  • Carcinogens
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Ki-67 Antigen
  • RNA, Neoplasm
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Diethylstilbestrol
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases