PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma
PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma
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DOI：
10.1158/0008-5472-can-04-3913
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发表时间：
2005-04-01
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：
Saal, LH;Holm, K;Parsons, R
通过PTEN的缺失或PI3K催化亚基α (PIK3CA)的突变，磷脂酰肌醇3-激酶（PI3K）通路的失调在人类癌症中经常发生。我们在342例人类乳腺肿瘤样本和细胞系中发现了26%的PIK3CA突变，在肿瘤I期至IV期的频率大致相同。为了研究PTEN和PIK3CA之间的关系，我们生成了一个PTEN表达缺失的肿瘤队列，并将其与保留PTEN的匹配对照组进行了比较。观察到PIK3CA突变与PTEN蛋白表达保持之间存在高度显著的关联。此外，PIK3CA突变与雌激素和孕激素受体（ER/PR）表达、淋巴结转移和ERBB2过表达有关。PIK3CA突变和PTEN缺失几乎是相互排斥的，这一事实表明，在很大一部分乳腺癌中，失调的磷脂酰肌醇-3,4,5-三磷酸WIN对肿瘤发生至关重要，PIP3稳态的丧失通过取消PIK3CA或PTEN来减轻靶向其他基因的选择压力。PIK3CA突变与ER/ pr阳性肿瘤的相关性以及PTEN缺失与ER/ pr阴性肿瘤的相关性证明了肿瘤进化的不同分支。此外，ERBB2过表达与PIK3CA突变之间的关联表明，要克服完整的PTEN，可能需要多个激活PI3K/AKT通路的输入。因此，PIK3CA突变是常见的，发生在癌症发展的早期，并具有预后和治疗意义。
Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway either through loss of PTEN or mutation of the catalytic subunit alpha of PI3K (PIK3CA) occurs frequently in human cancer. We identified PIK3CA mutations in 26% of 342 human breast tumor samples and cell lines at about equal frequency in tumor stages I to IV. To investigate the relationship between PTEN and PIK3CA, we generated a cohort of tumors that had lost PTEN expression and compared it with a matched control set that had retained PTEN. A highly significant association between PIK3CA mutations and retention of PTEN protein expression was observed. In addition, PIK3CA mutations were associated with expression of estrogen and progesterone receptors (ER/PR), lymph node metastasis, and ERBB2 overexpression. The fact that PIK3CA mutations and PTEN loss are nearly mutually exclusive implies that deregulated phosphatidylinositol-3,4,5-triphosphate WIN is critical for tumorigenesis in a significant fraction of breast cancers and that loss Of PIP3 homeostasis by abrogation of either PIK3CA or PTEN relieves selective pressure for targeting of the other gene. The correlation of PIK3CA mutation to ER/PR-positive tumors and PTEN loss to ER/PR-negative tumors argues for disparate branches of tumor evolution. Furthermore, the association between ERBB2 overexpression and PIK3CA mutation implies that more than one input activating the PI3K/AKT pathway may be required to overcome intact PTEN. Thus, mutation of PIK3CA is frequent, occurs early in carcinoma development, and has prognostic and therapeutic implications.