Department of Pathology, Science Park Research Division, The University of Texas M.D. Anderson Cancer Center, 1808 Park Road 1C, Smithville, TX 78957, USA.
Cancer Prev Res (Phila). 2010 Mar;3(3):290-300. doi: 10.1158/1940-6207.CAPR-09-0199. Epub 2010 Feb 23.
Insulin-like growth factor-I receptor signaling contributes to the development of endometrial hyperplasia, the precursor to endometrioid-type endometrial carcinoma, in humans and in rodent models. This pathway is under both positive and negative regulation, including S6 kinase (S6K) phosphorylation of insulin receptor substrate-1 (IRS-1) at S636/639, which occurs downstream of mammalian target of rapamycin (mTOR) activation to inhibit this adapter protein. We observed activation of mTOR with a high frequency in human endometrial hyperplasia and carcinoma, but an absence of IRS-1 phosphorylation, despite high levels of activated S6K. To explore when during disease progression mammalian target of rapamycin (mTOR) activation and loss of negative feedback to IRS-1 occurred, we used the Eker rat (Tsc2(Ek/+)) model, where endometrial hyperplasia develops as a result of loss of Tsc2, a "gatekeeper" for mTOR. We observed mTOR activation early in progression in hyperplasias and in some histologically normal epithelial cells, suggesting that event(s) in addition to loss of Tsc2 were required for progression to hyperplasia. In contrast, whereas IRS-1 S636/639 phosphorylation was observed in normal epithelium, it was absent from all hyperplasias, indicating loss of IRS-1 inhibition by S6K occurred during progression to hyperplasia. Treatment with a mTOR inhibitor (WAY-129327) significantly decreased hyperplasia incidence and proliferative indices. Because progression from normal epithelium to carcinoma proceeds through 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.
胰岛素样生长因子-I 受体信号通路促进了子宫内膜增生的发生，而子宫内膜增生是子宫内膜样型子宫内膜癌的前期病变，这在人和啮齿动物模型中均有体现。该通路受到正、负调控，包括 S6 激酶（S6K）对胰岛素受体底物-1（IRS-1）S636/639 位的磷酸化，这一过程发生在哺乳动物雷帕霉素靶蛋白（mTOR）激活的下游，从而抑制该衔接蛋白。我们观察到在人类子宫内膜增生和癌中 mTOR 频繁激活，但 IRS-1 并未发生磷酸化，尽管 S6K 高度激活。为了探究在疾病进展过程中 mTOR 何时被激活以及 IRS-1 失去负反馈，我们使用 Eker 大鼠（Tsc2(Ek/+)）模型，该模型中由于 Tsc2 的缺失导致了子宫内膜增生，Tsc2 是 mTOR 的“守门员”。我们观察到在增生早期以及部分组织学正常的上皮细胞中 mTOR 被激活，这表明除 Tsc2 缺失之外，还有其它事件导致了增生的发生。相反，IRS-1 S636/639 位磷酸化在正常上皮中观察到，但在所有增生中均缺失，这表明在向增生进展过程中 S6K 导致 IRS-1 抑制的丧失。用 mTOR 抑制剂（WAY-129327）治疗显著降低了增生的发生率和增殖指数。由于从正常上皮到癌的进展是通过子宫内膜增生发生的，这些数据提示了一个进展序列，即 mTOR 的激活先于 IRS-1 负反馈的丧失，这发生在该疾病发展的初始阶段。
