Mosley Jonathan D, Poirier John T, Seachrist Darcie D, Landis Melissa D, Keri Ruth A
Department of Pharmacology, CWRU School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4965, USA.
Mol Cancer Ther. 2007 Aug;6(8):2188-97. doi: 10.1158/1535-7163.MCT-07-0235.
Amplification of the HER2 (ErbB2, c-Neu) proto-oncogene in breast cancer is associated with poor prognosis and high relapse rates. HER2/ErbB2, in conjunction with ErbB3, signals through the Akt/phosphatidylinositol 3-kinase pathway and leads to the activation of mammalian target of rapamycin (mTOR), a critical mRNA translation regulator that controls cell growth. Gene expression analysis of mammary tumors collected from mouse mammary tumor virus-c-Neu transgenic mice revealed that mRNA levels of several mTOR pathway members were either up-regulated (p85/phosphatidylinositol 3-kinase and p70S6 kinase) or down-regulated (eIF-4E-BP1) in a manner expected to enhance signaling through this pathway. Treatment of these mice with the mTOR inhibitor rapamycin caused growth arrest and regression of primary tumors with no evidence of weight loss or generalized toxicity. The treatment effects were due to decreased proliferation, associated with reduced cyclin D1 expression, and increased cell death in primary tumors. Whereas many of the dead epithelial cells had the histopathologic characteristics of ischemic necrosis, rapamycin treatment was not associated with changes in microvascular density or apoptosis. Rapamycin also inhibited cellular proliferation in lung metastases. In summary, data from this preclinical model of ErbB2/Neu-induced breast cancer show that inhibition of the mTOR pathway with rapamycin blocks multiple stages of ErbB2/Neu-induced tumorigenic progression.
乳腺癌中HER2（ErbB2，c-Neu）原癌基因的扩增与预后不良和高复发率相关。HER2/ErbB2与ErbB3共同作用，通过Akt/磷脂酰肌醇3-激酶途径发出信号，导致哺乳动物雷帕霉素靶蛋白（mTOR）激活，mTOR是一种控制细胞生长的关键mRNA翻译调节因子。对从小鼠乳腺肿瘤病毒-c-Neu转基因小鼠收集的乳腺肿瘤进行基因表达分析发现，几种mTOR途径成员的mRNA水平要么上调（p85/磷脂酰肌醇3-激酶和p70S6激酶），要么下调（eIF-4E-BP1），其方式预期会增强通过该途径的信号传导。用mTOR抑制剂雷帕霉素治疗这些小鼠导致原发性肿瘤生长停滞和消退，没有体重减轻或全身毒性的迹象。治疗效果归因于增殖减少，这与细胞周期蛋白D1表达降低相关，以及原发性肿瘤中细胞死亡增加。虽然许多死亡的上皮细胞具有缺血性坏死的组织病理学特征，但雷帕霉素治疗与微血管密度或细胞凋亡的变化无关。雷帕霉素还抑制肺转移中的细胞增殖。总之，来自这个ErbB2/Neu诱导的乳腺癌临床前模型的数据表明，用雷帕霉素抑制mTOR途径可阻断ErbB2/Neu诱导的肿瘤发生进展的多个阶段。
