An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.
An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.
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DOI：
10.1158/0008-5472.can-07-6854
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发表时间：
2008-08-01
期刊：
影响因子：
11.2
通讯作者：
Hennessy BT
中科院分区：
文献类型：
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作者：
Stemke-Hale K;Gonzalez-Angulo AM;Lluch A;Neve RM;Kuo WL;Davies M;Carey M;Hu Z;Guan Y;Sahin A;Symmans WF;Pusztai L;Nolden LK;Horlings H;Berns K;Hung MC;van de Vijver MJ;Valero V;Gray JW;Bernards R;Mills GB;Hennessy BT
磷脂酰肌醇3-激酶（PI 3 K）/AKT通路畸变在癌症中很常见。通过将基于质谱的测序和反相蛋白阵列应用于547个人乳腺癌和41个细胞系，我们确定了PIK 3CA、AKT和PTEN突变的亚型特异性和信号传导效应，以及PIK 3CA突变对体外PI 3 K抑制反应性和辅助他莫昔芬后结果的影响。PIK 3CA突变在激素受体阳性（34.5%）和HER 2阳性（22.7%）中比基底细胞样肿瘤（8.3%）更常见。AKT 1（1.4%）和PTEN（2.3%）突变仅限于激素受体阳性癌症。与细胞系中不存在的AKT 1突变不同，PIK 3CA（39%）和PTEN（20%）突变在细胞系中比肿瘤中更常见，这表明在适应培养过程中对这些突变而不是AKT 1突变进行了选择。在157例激素受体阳性乳腺癌患者中，PIK 3CA突变对他莫昔芬辅助治疗后的结果没有显著影响。与PTEN缺失和AKT 1突变相比，PIK 3CA突变与肿瘤和细胞系中AKT和下游PI 3 K/AKT信号传导的显著较少和不一致的激活相关。PTEN丢失和PIK 3CA突变通常是一致的，表明对病理生理学的不同贡献。与PIK 3CA突变相比，PTEN缺失使细胞对PI 3 K抑制剂LY 294002的生长抑制显著更敏感。因此，PI 3 K通路畸变可能在不同乳腺癌亚型的发病机制中发挥不同的作用。存在的特定畸变可能对激素受体阳性乳腺癌中PI 3 K靶向治疗的选择具有影响。
Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy–based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor–positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor–positive cancers. Unlike AKT1 mutations that were absent from cell lines, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant effect on outcome after adjuvant tamoxifen therapy in 157 hormone receptor–positive breast cancer patients. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines. PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss rendered cells significantly more sensitive to growth inhibition by the PI3K inhibitor LY294002 than did PIK3CA mutations. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration present may have implications for the selection of PI3K-targeted therapies in hormone receptor–positive breast cancer.