title: Developmental reprogramming of IGF signaling and susceptibility to endometrial hyperplasia in the rat.
abstract: 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.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Adrienne S
authors.initials: AS
authors.lastname: McCampbell
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Walker
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Cook
authors.forename: Peter J A
authors.initials: PJ
authors.lastname: Davies
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002273:Carcinogens; D004054:Diethylstilbestrol; D004714:Endometrial Hyperplasia / Q000139:chemically induced* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D019394:Ki-67 Antigen / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis / Q000302:isolation & purification; D051381:Rats; D011922:Rats, Mutant Strains; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002273:Carcinogens; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D019394:Ki-67 Antigen; D012334:RNA, Neoplasm; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D004054:Diethylstilbestrol; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases