Department of Biochemistry, Boston University School of Medicine, MA, USA.
Oncogene. 2011 Jun 23;30(25):2836-45. doi: 10.1038/onc.2011.5. Epub 2011 Feb 7.
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 because of 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 (KO) 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 has an essential role in Her2-induced tumorigenesis by regulating oncogene-induced senescence pathways.
主要热休克蛋白 Hsp72 在许多人类癌症中高水平表达，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。在未转化的 MCF10A 乳腺上皮细胞中表达 Her2 导致转化，这可通过培养物中的焦点形成和异种移植物中的肿瘤发生来判断。然而，在 Hsp72 耗尽的细胞中表达 Her2 未能诱导转化。Hsp72 下调的抗肿瘤作用与细胞衰老有关，因为 p21 的积累和 survivin 的耗竭。因此，p21 的敲低或 survivin 的表达均可逆转这种衰老过程。此外，我们开发了一种与 Her2 表达相关的 Hsp72 依赖性乳腺癌动物模型。Hsp72 的敲除（KO）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 KO 小鼠中，表达 Her2 而不是乳腺组织增生导致导管发育受阻和肺泡芽缺失。这些作用是由于乳腺组织中大量的细胞衰老，这与 p21 的上调和 survivin 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。
