Heat shock protein Hsp72 plays an essential role in Her2-induced mammary tumorigenesis.
Heat shock protein Hsp72 plays an essential role in Her2-induced mammary tumorigenesis.
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DOI：
10.1038/onc.2011.5
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发表时间：
2011-06-23
期刊：
影响因子：
8
通讯作者：
Sherman, M. Y.
中科院分区：
文献类型：
--
作者：
Meng, L.;Hunt, C.;Yaglom, J. A.;Gabai, V. L.;Sherman, M. Y.
主要的热休克蛋白Hsp72在许多人类癌症中以升高的水平表达，并且其表达与肿瘤进展相关。在这里，我们研究了Hsp72在Her2癌基因诱导的肿瘤转化和肿瘤发生中的作用。Her2在未转化的MCF 10A乳腺上皮细胞中的表达引起转化，如通过培养物中的病灶形成和异种移植物中的肿瘤发生所判断的。然而，Her2在Hsp72耗尽的细胞中的表达未能诱导转化。Hsp72下调的抗肿瘤作用与细胞衰老有关，这是由于p21的积累和生存素的耗尽。因此，p21的敲低或存活素的表达逆转了这种衰老过程。此外，我们开发了与Her2表达相关的Hsp72依赖性乳腺癌的动物模型。Hsp72的敲除几乎完全抑制了MMTVneu乳腺癌小鼠模型中的肿瘤发生。在年轻的Hsp72基因敲除小鼠中，Her2的表达而不是乳腺组织增生导致导管发育的抑制和肺泡出芽的阻断。这些作用是由于乳腺组织中大量细胞衰老，这与p21的上调和生存素的下调有关。因此，Hsp72通过调节癌基因诱导的衰老途径在Her2诱导的肿瘤发生中起重要作用。
The major heat shock protein Hsp72 is expressed at elevated levels in many human cancers and its expression correlates with tumor progression. Here we investigated the role of Hsp72 in Her2 oncogene-induced neoplastic transformation and tumorigenesis. Expression of Her2 in untransformed MCF10A mammary epithelial cells caused transformation, as judged by foci formation in culture and tumorigenesis in xenografts. However, expression of Her2 in Hsp72-depleted cells failed to induce transformation. The anti-tumorigenic effects of Hsp72 downregulation were associated with cellular senescence due to accumulation of p21 and depletion of survivin. Accordingly, either knockdown of p21 or expression of survivin reversed this senescence process. Further, we developed an animal model of Hsp72-dependent breast cancer associated with expression of Her2. Knockout of Hsp72 almost completely suppressed tumorigenesis in the MMTVneu breast cancer mouse model. In young Hsp72 KO mice, expression of Her2 instead of mammary tissue hyperplasia led to suppression of duct development and blocked alveolar budding. These effects were due to massive cell senescence in mammary tissue, which was associated with upregulation of p21 and downregulation of survivin. Therefore Hsp72 plays an essential role in Her2-induced tumorigenesis by regulating oncogene-induced senescence pathways.
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影响因子：
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