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.

Microarray pathway analysis indicated that mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin growth factor 1 signaling pathways were inhibited by small interfering RNA against AT‑rich interactive domain 1A in endometrial cancer

“…IRS1 is an upstream component of the MAPK/ERK and the IGF-1 signaling pathways and is associated with a susceptibility to insulin resistance. Global activation of IGF-IR signaling and loss of negative feedback to IRS-1 appear to be reprogrammed in endometrial hyperplasia (18). IGF1R is overexpressed in the majority of malignant tissues, where it binds IGF to function as an anti-apoptotic agent by enhancing cell survival (19,20).…”

Effect of stem cell application on Asherman Syndrome, an experimental rat model

“…In each field, 100 epithelial cells were selected and viewed. The PCNA and Ki-67 indexes were expressed as percent of positive cells [10,11].…”

Targeting the mTOR/4E-BP Pathway in Endometrial Cancer

“…Several groups have also investigated the role of small-molecule mTOR kinase inhibitors in endometrial cancer cell lines (59,63) and the effects of mTOR inhibitors on mouse models of endometrial cancer (3,(64)(65)(66).…”

“…Mirroring human studies, tissue culture studies have shown contradictory results with regard to the impact of PTEN status on rapamycin sensitivity (32,40,41,43). Investigators have also examined rapalog treatment in mouse models of endometrial hyperplasia, and they found that treatment with rapalogs reduced tumor burden, slowed progression of disease, and decreased the incidence of hyperplastic lesions in mice predisposed to hyperplasia (3,(64)(65)(66).…”