The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours
The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours
复制标题
DOI：
10.1007/s10549-005-9017-7
复制
发表时间：
2006-02-01
影响因子：
3.8
通讯作者：
Kallioniemi, A
中科院分区：
文献类型：
--
作者：
Rauta, J;Alarmo, EL;Kallioniemi, A
丝氨酸-苏氨酸蛋白磷酸酶 PPM1D 可能在肿瘤发生中发挥重要作用。通过 p38 MAPK 的失活，PPM1D 充当 p53 肿瘤抑制基因的负反馈调节因子，并控制其他细胞周期调节蛋白（例如 CCND1）的表达。此外，最近的敲除小鼠研究表明 PPM1D 参与 p16 表达和 RB 肿瘤抑制途径的调节。在这里，我们探讨了 PPM1D 畸变在原发性乳腺癌中的作用。 PPM1D 拷贝数分析显示 11% (13/117) 的肿瘤出现扩增，定量实时 RT-PCR 显示 PPM1D 扩增与表达增加之间存在显着相关性 (p=0.0148)。 PPM1D 扩增几乎只发生在野生型 p53 的肿瘤中，表明这些事件是相互排斥的，并进一步证实了 PPM1D 作为 p53 负调节因子的作用。有趣的是，PPM1D 扩增与 ERBB2 表达相关（p=0.0001），因此意味着 PPM1D 畸变发生在预后不良的肿瘤中。我们还探讨了 PPM1D 两个可能的下游靶标的表达水平。然而，免疫组织化学分析显示，有或没有 PPM1D 畸变的肿瘤中 CCND1 和 p16 蛋白的染色模式没有差异，因此表明先前来自动物模型实验的数据不能直接转移到原发性人类肿瘤。另一方面，这些关键细胞蛋白可能在乳腺癌中通过复杂的方式受到调节，显然 PPM1D 仅代表其中一种机制。总而言之，我们的研究结果证实了 PPM1D 在乳腺癌中的重要作用。
The serine-threonine protein phosphatase PPM1D is likely to play an important role in tumorigenesis. Through inactivation of p38 MAPK, PPM1D acts as a negative feedback regulator of p53 tumour suppressor gene and controls the expression of other cell cycle regulatory proteins, such as CCND1. In addition, recent knock-out mouse studies implicated PPM1D in the regulation of p16 expression and the RB tumour suppressor pathway. Here we explored the role of PPM1D aberrations in primary breast cancer. PPM1D copy number analysis showed amplification in 11% (13/117) of the tumours and quantitative real-time RT-PCR revealed a significant correlation (p=0.0148) between PPM1D amplification and increased expression. PPM1D amplification occurred almost exclusively in tumours with wild-type p53 suggesting that these events are mutually exclusive and further confirming the role of PPM1D as a negative regulator of p53. Interestingly, PPM1D amplification was associated with ERBB2 expression (p=0.0001) thus implying that PPM1D aberrations occurs in tumours with poor prognosis. We also explored the expression levels of two possible downstream targets of PPM1D. However, immunohistochemical analyses revealed no differences in the staining patterns of CCND1 and p16 proteins in tumours with or without PPM1D aberrations, thus suggesting that previous data from animal model experiments is not directly transferable to primary human tumours. On the other hand, these key cellular proteins are likely to be regulated through a complex fashion in breast cancer and apparently PPM1D represents only one of these mechanisms. Taken together, our findings substantiate an important role for PPM1D in breast cancer.