Molecular Insights of Pathways Resulting from Two Common PIK3CA Mutations in Breast Cancer
Molecular Insights of Pathways Resulting from Two Common PIK3CA Mutations in Breast Cancer
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DOI：
10.1158/0008-5472.can-15-3174
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发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Nakshatri, Harikrishna
中科院分区：
文献类型：
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作者：
Bhat-Nakshatri, Poornima;Goswami, Chirayu P.;Nakshatri, Harikrishna
PI 3 K通路在大约70%的乳腺癌中被激活。影响PI 3 K p110 α亚基的PIK 3CA基因突变或扩增在20%至40%的病例中导致该途径的激活，特别是在雌激素受体α（ER α）阳性乳腺癌中。AKT激酶家族AKT 1 -3是PI 3 K的下游靶点，这些激酶激活ER α。尽管已经开发了几种PI 3 K抑制剂，但没有一种在临床上被证明是有效的，部分原因是对PI 3 K信号传导至特定AKT亚型的选择性途径的不完全理解。因此，我们在本研究中调查了特定AKT亚型在连接PI 3 K活化与ER α信号传导中的作用，并且我们还评估了使用PI 3 K-AKT亚型-ER α信号传导轴的组分作为对PI 3 K抑制剂的反应的预测标志物的效用。使用具有确定的天然或敲入PIK 3CA突变和/或PI 3 K超活化的各种生理学相关模型系统，我们表明PIK 3CA-E545 K突变（在类似于20%的PIK 3CA突变型乳腺癌中发现）而不是PIK 3CA-H1047 R突变（在55%的PIK 3CA突变型乳腺癌中发现）优先激活AKT 1。我们的研究结果表明，在具有PIK 3CA-E545 K突变的乳腺癌细胞中，需要AKT 1信号传导来响应雌激素和PI 3 K抑制剂，但在具有其他PIK 3CA突变的乳腺癌细胞中则不然。这项研究提供的证据表明，ER阳性乳腺癌的个性化治疗PI 3 K抑制剂治疗可能受益于PIK 3CA-E545 K-AKT 1-雌激素信号通路的分析。(C)2016年AACR。
The PI3K pathway is activated in approximately 70% of breast cancers. PIK3CA gene mutations or amplifications that affect the PI3K p110 alpha subunit account for activation of this pathway in 20% to 40% of cases, particularly in estrogen receptor alpha (ER alpha)-positive breast cancers. AKT family of kinases, AKT1-3, are the downstream targets of PI3K and these kinases activate ER alpha. Although several inhibitors of PI3K have been developed, none has proven effective in the clinic, partly due to an incomplete understanding of the selective routing of PI3K signaling to specific AKT isoforms. Accordingly, we investigated in this study the contribution of specific AKT isoforms in connecting PI3K activation to ER alpha signaling, and we also assessed the utility of using the components of PI3K-AKT isoform-ER alpha signaling axis as predictive biomar-kers of response to PI3K inhibitors. Using a variety of physiologically relevant model systems with defined natural or knock-in PIK3CA mutations and/or PI3K hyperactivation, we show that PIK3CA-E545K mutations (found in similar to 20% of PIK3CA-mutant breast cancers), but not PIK3CA-H1047R mutations (found in 55% of PIK3CA-mutant breast cancers), preferentially activate AKT1. Our findings argue that AKT1 signaling is needed to respond to estrogen and PI3K inhibitors in breast cancer cells with PIK3CA-E545K mutation, but not in breast cancer cells with other PIK3CA mutations. This study offers evidence that personalizing treatment of ER-positive breast cancers to PI3K inhibitor therapy may benefit from an analysis of PIK3CA-E545K-AKT1-estrogen signaling pathways. (C) 2016 AACR.