Antitumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancer
Antitumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancer
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DOI：
10.1158/0008-5472.can-04-4589
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发表时间：
2005-06-15
期刊：
影响因子：
11.2
通讯作者：
Abraham, RT
中科院分区：
文献类型：
--
作者：
Liu, M;Howes, A;Abraham, RT
ErbB2(Neu)受体酪氨酸激酶在人类乳腺癌中经常过度表达，这种表型与不良的临床预后相关。在缺乏或存在第二个编码血管内皮生长因子(VEGF)转基因基因的情况下，我们检测了哺乳动物靶标雷帕霉素对携带激活的ErbB2(NeuYD)转基因小鼠乳腺肿瘤形成的影响。用雷帕霉素治疗NeuYD或NeuYD X VEGF小鼠可显著抑制肿瘤生长，同时显著减少肿瘤血管生成。雷帕霉素抗肿瘤活性的两个关键事件可能是ErbB3表达减少和低氧应激抑制低氧诱导因子-1依赖的反应。在标准的单层培养中，雷帕霉素仅对肿瘤来源的细胞系的增殖产生轻微的抑制作用，但在三维培养中，雷帕霉素显著抑制了相同细胞的生长，部分原因是诱导了凋亡细胞死亡。这些研究强调了哺乳动物靶标雷帕霉素抑制剂对ErbB2阳性乳腺癌的治疗潜力，并表明，与单层培养相比，三维细胞培养在研究雷帕霉素及其相关化合物的抗肿瘤机制方面具有更好的体外模型。
The ErbB2 (Neu) receptor tyrosine kinase is frequently over-expressed in human breast cancers, and this phenotype correlates with a poor clinical prognosis. We examined the effects of the mammalian target of rapamycin inhibitor, rapamycin, on mammary tumorigenesis in transgenic mice bearing an activated ErbB2 (NeuYD) transgene in the absence or presence of a second transgene encoding vascular endothelial growth factor (VEGF). Treatment of NeuYD or NeuYD X VEGF mice with rapamycin dramatically inhibited tumor growth accompanied by a marked decrease in tumor vascularization. Two key events that may underlie the antitumor activity of rapamycin were decreased expression of ErbB3 and inhibition of hypoxia-inducible factor-1-dependent responses to hypoxic stress. Rapamycin exposure caused only a modest inhibition of the proliferation of tumor-derived cell lines in standard monolayer cultures, but dramatically inhibited the growth of the same cells in three-dimensional cultures, due in part to the induction of apoptotic cell death. These studies underscore the therapeutic potential of mammalian target of rapamycin inhibitors in ErbB2-positive breast cancers and indicate that, relative to monolayer cultures, three-dimensional cell cultures are more predictive in vitro models for studies of the antitumor mechanisms of rapamycin and related compounds.