Loss of inhibitory insulin receptor substrate-1 phosphorylation is an early event in mammalian target of rapamycin-dependent endometrial hyperplasia and carcinoma.
Loss of inhibitory insulin receptor substrate-1 phosphorylation is an early event in mammalian target of rapamycin-dependent endometrial hyperplasia and carcinoma.
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DOI：
10.1158/1940-6207.capr-09-0199
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发表时间：
2010-03
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影响因子：
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通讯作者：
Broaddus RR
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文献类型：
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作者：
McCampbell AS;Harris HA;Crabtree JS;Winneker RC;Walker CL;Broaddus RR
IGF-I受体信号传导有助于人类和啮齿动物模型中子宫内膜增生的发展，子宫内膜增生是子宫内膜样癌的前体。该途径处于正调控和负调控下，包括IRS-1在丝氨酸（636/639）处的S6 K磷酸化，其发生在mTOR活化的下游以抑制该衔接蛋白。我们观察到在人子宫内膜增生和癌中mTOR的高频率激活，但IRS-1磷酸化的缺乏，尽管激活的S6 K水平高。为了探索在疾病进展过程中何时发生mTOR激活和IRS-1负反馈的丧失，我们利用Eker大鼠（Tsc 2 Ek/+）模型，其中子宫内膜增生由于Tsc 2（mTOR的“看门人”）的丧失而发展。我们在增生和一些组织学正常的上皮细胞中观察到mTOR活化早期进展，表明除了Tsc 2丢失之外的事件是进展为增生所必需的。相反，虽然IRS-1 S636/639磷酸化在正常上皮中观察到，但在所有增生中均不存在，表明S6 K对IRS-1抑制的丧失发生在增生进展期间。用mTOR抑制剂（WAY-129327）治疗显著降低增生发生率和增殖指数。由于从正常上皮到癌的进展是通过子宫内膜增生进行的，这些数据表明在这种疾病发展的初始阶段，mTOR的激活之后是IRS-1负反馈的丧失。
IGF-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 S6K phosphorylation of IRS-1 at serine (636/639), which occurs downstream of 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 mTOR activation and loss of negative feedback to IRS-1 occurred, we utilized the Eker rat (Tsc2Ek/+) 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, while 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 an mTOR inhibitor (WAY-129327) significantly decreased hyperplasia incidence and proliferative indices. Since progression from normal epithelium to carcinoma proceeds via 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.