A Pin1/Mutant p53 Axis Promotes Aggressiveness in Breast Cancer
A Pin1/Mutant p53 Axis Promotes Aggressiveness in Breast Cancer
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DOI：
10.1016/j.ccr.2011.06.004
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发表时间：
2011-07-12
期刊：
影响因子：
50.3
通讯作者：
Del Sal, Giannino
中科院分区：
文献类型：
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作者：
Girardini, Javier E.;Napoli, Marco;Del Sal, Giannino
TP53错义突变显著影响肿瘤进展，但其作用机制尚不清楚。在这里，我们证明了脯氨酸异构酶Pin1在突变型p53致癌功能中的基本作用。Pin1在Li-Fraumeni小鼠模型中促进肿瘤发生，并在ras依赖性转化中与p53突变体合作。在乳腺癌细胞中，Pin1促进突变型p53依赖于抗转移因子p63的抑制，并诱导突变型p53转录程序增加侵袭性。此外，我们确定了与乳腺癌预后不良相关的转录特征，并且在一组患者中，Pin1过表达影响p53突变的预后价值。这些结果确定了Pin1/突变p53轴，该轴传递致癌信号以促进人类癌症的侵袭性。
TP53 missense mutations dramatically influence tumor progression, however, their mechanism of action is still poorly understood. Here we demonstrate the fundamental role of the prolyl isomerase Pin1 in mutant p53 oncogenic functions. Pin1 enhances tumorigenesis in a Li-Fraumeni mouse model and cooperates with mutant p53 in Ras-dependent transformation. In breast cancer cells, Pin1 promotes mutant p53 dependent inhibition of the antimetastatic factor p63 and induction of a mutant p53 transcriptional program to increase aggressiveness. Furthermore, we identified a transcriptional signature associated with poor prognosis in breast cancer and, in a cohort of patients, Pin1 overexpression influenced the prognostic value of p53 mutation. These results define a Pin1/mutant p53 axis that conveys oncogenic signals to promote aggressiveness in human cancers.