Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers
Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers
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DOI：
10.1158/1078-0432.ccr-04-0112
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发表时间：
2004-10-15
影响因子：
11.5
通讯作者：
Yu, DH
中科院分区：
文献类型：
--
作者：
Zhou, XY;Tan, M;Yu, DH
Akt/哺乳动物雷帕霉素靶蛋白（mTOR）/4 E-BP 1通路被认为是蛋白质合成的中心调节因子，涉及细胞增殖、分化和存活的调节。作为抗癌试剂的mTOR抑制剂在包括乳腺癌在内的各种恶性肿瘤中正在进行积极的评估。然而，Akt/mTOR/4 E-BP 1通路的激活状态及其在乳腺癌中的潜在作用仍然未知。因此，我们用Akt、mTOR和4 E-BP 1磷酸化的特异性抗体通过免疫组织化学检测了165例浸润性乳腺癌，并将其与正常乳腺上皮、纤维腺瘤、导管内增生和导管原位癌进行了比较。我们发现Akt、mTOR和4 E-BP 1的磷酸化水平从正常乳腺上皮到增生和异常增生到肿瘤浸润逐渐增加。磷酸化Akt、mTOR和4 E-BP 1与ErbB 2过表达呈正相关。生存分析表明，这三个标志物中的每一个的磷酸化独立地与无病生存率差相关。在体外，我们进一步证实了ErbB 2过表达与mTOR激活之间的因果关系，这与侵袭能力增强和对mTOR抑制剂雷帕霉素的敏感性有关。我们的结果首次证明了以下内容：（a）乳腺癌中Akt、mTOR和4 E-BP 1的高水平磷酸化，表明Akt/mTOR/4 E-BP 1通路在乳腺癌发展和进展中的激活;（B）体外和体内乳腺癌中ErbB 2和Akt/mTOR/4 E-BP 1通路之间的联系，表明Akt/mTOR活化在ErbB 2介导的乳腺癌进展中的可能作用;和（c）该途径在预测乳腺癌患者，特别是用mTOR抑制剂治疗的那些患者的预后中的潜在作用。
The Akt/mammalian target of rapamycin (mTOR)/4E-BP1 pathway is considered to be a central regulator of protein synthesis, involving the regulation of cell proliferation, differentiation, and survival. The inhibitors of mTOR as anticancer reagents are undergoing active evaluation in various malignancies including breast cancer. However, the activation status of the Akt/mTOR/4E-BP1 pathway and its potential roles in breast cancers remain unknown. Thus, we examined 165 invasive breast cancers with specific antibodies for the phosphorylation of Akt, mTOR, and 4E-BP1 by immunohistochemistry and compared them with normal breast epithelium, fibroadenoma, intraductal hyperplasia, and ductal carcinoma in situ. We discovered that the phosphorylation of Akt, mTOR, and 4E-BP1 increased progressively from normal breast epithelium to hyperplasia and abnormal hyperplasia to tumor invasion. Phosphorylated Akt, mTOR, and 4E-BP1 were positively associated with ErbB2 overexpression. Survival analysis showed that phosphorylation of each of these three markers was associated with poor disease-free survival independently. In vitro, we further confirmed the causal relationship between ErbB2 overexpression and mTOR activation, which was associated with enhanced invasive ability and sensitivity to a mTOR inhibitor, rapamycin. Our results, for the first time, demonstrate the following: (a) high levels of phosphorylation of Akt, mTOR, and 4E-BP1 in breast cancers, indicating activation of the Akt/mTOR/4E-BP1 pathway in breast cancer development and progression; (b) a link between ErbB2 and the Akt/mTOR/4E-BP1 pathway in breast cancers in vitro and in vivo, indicating the possible role of Akt/mTOR activation in ErbB2-mediated breast cancer progression; and (c) a potential role for this pathway in predicting the prognosis of patients with breast cancer, especially those treated with mTOR inhibitors.