Abstract A28: Loss of inhibitory IRS-1 phosphorylation is an early event in mTOR-dependent endometrial hyperplasia and carcinoma

Abstracts: Frontiers in Cancer Prevention Research 2008 A28 Activation of IGF-I receptor signaling contributes to the development of endometrioid-type endometrial carcinoma in humans and in rodent models. This signaling pathway is under both positive and negative regulation, including S6K phosphorylation of IRS-1 at S636/639, which occurs downstream of mTOR activation to inhibit this adapter protein. We observed activation of mTOR signaling with a high frequency in human endometrial hyperplasia and carcinoma, but an absence of IRS1 phosphorylation at S636/639, despite the high levels of activated S6K in these tumors. To explore when during disease progression mTOR activation and loss of inhibitory IRS-1 phosphorylation occurred, we utilized the Eker rat (Tsc2Ek/+) model for this disease, where endometrial hyperplasia develops as a result of loss of Tsc2, the “gatekeeper” for mTOR signaling. We observed mTOR activation early in progression in hyperplasias and in some histologically normal appearing epithelial cells, suggesting that event(s) in addition to loss of Tsc2 were required for progression to hyperplasia. In contrast, IRS-1 phosphorylation at S636/639 was observed in normal appearing epithelium, but was absent from all hyperplasias, indicating loss of IRS-1 inhibition by S6K occurred during progression to hyperplasia. Furthermore, treatment of Eker rats with an mTOR inhibitor resulted in a decreased incidence of endometrial hyperplasia [54/79 hyperplasias/uterine cross section in vehicle controls to 6/90 in treated rats (p 95% (p < 0.05). Since progression from normal epithelium to endometrial carcinoma proceeds via the intermediate step of endometrial hyperplasia, these data suggest a progression sequence where activation of mTOR is followed by loss of negative feedback to IRS-1 during the initial stages of development of this disease. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A28.