3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma.
3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma.
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DOI：
10.1158/0008-5472.can-09-0820
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发表时间：
2009-08-01
期刊：
影响因子：
11.2
通讯作者：
Parsons R
中科院分区：
文献类型：
--
作者：
Maurer M;Su T;Saal LH;Koujak S;Hopkins BD;Barkley CR;Wu J;Nandula S;Dutta B;Xie Y;Chin YR;Kim DI;Ferris JS;Gruvberger-Saal SK;Laakso M;Wang X;Memeo L;Rojtman A;Matos T;Yu JS;Cordon-Cardo C;Isola J;Terry MB;Toker A;Mills GB;Zhao JJ;Murty VV;Hibshoosh H;Parsons R
ERBB2、PTEN和PIK3CA的损伤通过增加磷脂酰肌醇-3，4，5-三磷酸(PIP3)的水平在癌症发展过程中激活PI3K途径。3-磷酸肌醇依赖的激酶1(PDK1)是PI3K信号输出的第一个节点，是激活AKT所必需的。PIP3通过与它们的PH结构域相互作用将PDK1和AKT招募到细胞膜上，允许PDK1通过在残基苏氨酸308处磷酸化AKT来激活AKT。我们发现，在大多数人类乳腺癌中，总的PDK1蛋白和mRNA过度表达，21%的肿瘤具有编码PDK1、PDPK1的基因的五个或更多拷贝。我们发现，PDPK1拷贝数的增加与上游通路损害(ERBB2扩增、PTEN缺失或PIK3CA突变)以及患者的生存有关。对一组独立的乳腺癌和来自多种形式的人类癌症的肿瘤细胞株的检查也发现，PDK1蛋白水平与这种上游通路损伤有关。在人乳腺细胞中，PDK1增强了上游病变向AKT发出信号的能力，刺激细胞生长和迁移，并使细胞对PDK1和PI3K抑制更具抵抗力。原位移植后，PDK1的过度表达不是致癌的，但显著增强了ERBB2的成瘤能力。我们的研究认为，PDK1的过度表达和PDPK1拷贝数的增加是癌症中常见的现象，它们增强了上游病变对PI3K途径的致癌作用。因此，我们得出结论，PDK1的改变是乳腺癌PI3K致癌信号的重要组成部分。
Lesions of ERBB2, PTEN, and PIK3CA activate the PI3K pathway during cancer development by increasing levels of phosphatidylinositol-3,4,5-triphosphate (PIP3). 3-phosphoinositide-dependent kinase 1 (PDK1) is the first node of the PI3K signal output and is required for activation of AKT. PIP3 recruits PDK1 and AKT to the cell membrane through interactions with their PH domains, allowing PDK1 to activate AKT by phosphorylating it at residue threonine 308. We show that total PDK1 protein and mRNA was over-expressed in a majority of human breast cancers and that 21% of tumors had five or more copies of the gene encoding PDK1, PDPK1. We found that increased PDPK1 copy number was associated with upstream pathway lesions (ERBB2 amplification, PTEN loss, or PIK3CA mutation), as well as patient survival. Examination of an independent set of breast cancers and tumor cell lines derived from multiple forms of human cancers also found increased PDK1 protein levels associated with such upstream pathway lesions. In human mammary cells, PDK1 enhanced the ability of upstream lesions to signal to AKT, stimulate cell growth and migration, and rendered cells more resistant to PDK1 and PI3K inhibition. After orthotopic transplantation, PDK1 overexpression was not oncogenic but dramatically enhanced the ability of ERBB2 to form tumors. Our studies argue that PDK1 overexpression and increased PDPK1 copy number are common occurrences in cancer that potentiate the oncogenic effect of upstream lesions on the PI3K pathway. Therefore, we conclude that alteration of PDK1 is a critical component of oncogenic PI3K signaling in breast cancer.