1. ¹Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2. ²Science Park Research Division, Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX, USA
3. ³Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, TX, USA

Correspondence: Dr Peter JA Davies, MD, PhD, Department of Integrative Biology and Pharmacology, MSB 5.104, University of Texas Houston Health Science Center, 6431 Fannin Street, Houston, TX 77030, USA. E-mail: Peter.J.Davies@uth.tmc.edu

Received 8 November 2007; Revised 20 February 2008; Accepted 20 February 2008; Published online 21 April 2008.

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.