Enhanced insulin signaling via Shc in human breast cancer
Enhanced insulin signaling via Shc in human breast cancer
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DOI：
10.1016/s0026-0495(03)00311-1
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发表时间：
2003-12-01
影响因子：
9.8
通讯作者：
Draznin, B
中科院分区：
文献类型：
--
作者：
Finlayson, CA;Chappell, J;Draznin, B
胰岛素是一种温和的有丝分裂原，已被证明可以增强其他生长因子对有丝分裂的影响。由于高胰岛素血症和/或胰岛素受体过度表达与乳腺癌的发生、发展和预后有关，我们试图评估这些联系的机制。我们比较了20例患者的乳腺肿瘤和邻近正常乳腺组织中胰岛素受体的表达和胰岛素信号的大小。我们观察到，与正常组织相比，肿瘤组织中的胰岛素结合量增加了一倍以上(通过配对测试，P<；.1)。根据Shc的磷酸化程度判断，向Shc发出的胰岛素信号在肿瘤中也显著增强。相反，在肿瘤组织和正常乳腺组织中，胰岛素受体底物-1(IRS-1)、Akt和丝裂原激活蛋白(MAP)激酶的磷酸化是相同的。最后，肿瘤显示出显著增加的法尼化p21RAS和香叶基香叶化Rho-A(P<；.1)，这与肿瘤组织中依赖Shc激活的法尼基(FTase)和香叶基香叶基转移酶(GGTase)是一致的。我们认为，与癌旁正常乳腺组织相比，乳腺癌组织中胰岛素受体表达增加、Shc优先过度磷酸化以及p21Ras和Rho-A先烯基化的增加可能是胰岛素影响乳腺癌有丝分裂的机制之一。(C)2003 Elsevier Inc.保留所有权利。
Insulin is a mild mitogen and has been shown to potentiate mitogenic influence of other growth factors. Because hyperinsulinema and/or overexpression of insulin receptors have been linked to development, progression, and outcome of breast cancer, we attempted to evaluate the mechanism of these associations. We have compared the expression of insulin receptors and the magnitude of insulin signaling in breast tumors and adjacent normal mammary tissue samples obtained from 20 patients. We observed that insulin binding more than doubled in the tumors as compared with the normal tissue (P < .1 by paired t est). Insulin signaling to Shc, judged by the magnitude of its phosphorylation, was also significantly enhanced in the tumors. In contrast, the phosphorylation of the insulin-receptor substrate-1 (IRS-1), Akt, and mitogen -activated protein (MAP) kinase were identical in the tumorous and normal mammary tissues. Finally, tumors displayed significantly increased amounts of farnesylated p21 Ras and geranylgeranylated Rho-A (P < .1), consistent with Shc-dependent activation of farnesyl (FTase) and geranylgeranyl transferases (GGTase) in the tumor tissue. We conclude that the mechanism of the mitogenic influence of insulin in breast cancer may include increased expression of insulin receptors, preferential hyperphosphorylation of Shc, and increased amounts of prenylated p21 Ras and Rho-A in tumor tissue as compared with adjacent normal mammary tissue. (C) 2003 Elsevier Inc. All rights reserved.