Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Oncogene. 2013 Feb 14;32(7):861-71. doi: 10.1038/onc.2012.105. Epub 2012 Apr 9.
Levels of eukaryotic initiation factor 4E (eIF4E) are frequently elevated in human cancers and in some instances have been associated with poor prognosis and outcome. Here we utilize transgenic and allograft breast cancer models to demonstrate that increased mammalian target of rapamycin (mTOR) signalling can be a significant contributor to breast cancer progression in vivo. Suppressing mTOR activity, as well as levels and activity of the downstream translation regulators, eIF4E and eIF4A, delayed breast cancer progression, onset of associated pulmonary metastasis in vivo and breast cancer cell invasion and migration in vitro. Translation of vascular endothelial growth factor (VEGF), matrix metallopeptidase 9 (MMP9) and cyclin D1 mRNAs, which encode products associated with the metastatic phenotype, is inhibited upon eIF4E suppression. Our results indicate that the mTOR/eIF4F axis is an important contributor to tumor maintenance and progression programs in breast cancer. Targeting this pathway may be of therapeutic benefit.
真核起始因子 4E（eIF4E）的水平在人类癌症中经常升高，在某些情况下与预后不良和结局相关。在这里，我们利用转基因和同种异体乳腺癌模型证明，增加哺乳动物雷帕霉素靶蛋白（mTOR）信号可以是体内乳腺癌进展的重要贡献者。抑制 mTOR 活性以及下游翻译调节剂 eIF4E 和 eIF4A 的水平和活性可延迟体内乳腺癌的进展、相关肺转移的发生以及体外乳腺癌细胞的侵袭和迁移。血管内皮生长因子（VEGF）、基质金属蛋白酶 9（MMP9）和细胞周期蛋白 D1 mRNA 的翻译被抑制，这些 mRNA 编码与转移表型相关的产物，当抑制 eIF4E 时。我们的结果表明，mTOR/eIF4F 轴是乳腺癌肿瘤维持和进展计划的重要贡献者。靶向该途径可能具有治疗益处。
