Integrative analysis of cyclin protein levels identifies cyclin b1 as a classifier and predictor of outcomes in breast cancer.
Integrative analysis of cyclin protein levels identifies cyclin b1 as a classifier and predictor of outcomes in breast cancer.
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DOI：
10.1158/1078-0432.ccr-08-3293
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发表时间：
2009-06-01
期刊：
影响因子：
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通讯作者：
Hennessy BT
中科院分区：
文献类型：
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作者：
Agarwal R;Gonzalez-Angulo AM;Myhre S;Carey M;Lee JS;Overgaard J;Alsner J;Stemke-Hale K;Lluch A;Neve RM;Kuo WL;Sorlie T;Sahin A;Valero V;Keyomarsi K;Gray JW;Borresen-Dale AL;Mills GB;Hennessy BT
我们研究了细胞周期蛋白B1、D1和E1的表达水平，以及细胞周期蛋白过度表达对由临床变量和转录谱定义的不同乳腺癌亚型患者预后的影响。
使用反相蛋白质阵列和/或转录谱分析对779个乳腺肿瘤和53个细胞系中的细胞周期蛋白B1、D1和E1的表达水平进行了定量。
细胞周期蛋白E1过度表达是三阴性和基底样肿瘤的特异性标志物，而细胞周期蛋白B1过度表达发生在预后不良的激素受体阳性、腔面B型和基底样乳腺癌中。细胞周期蛋白D1过度表达发生在腔面型和正常样癌症中。由细胞周期蛋白B1、D1和E1综合表达所定义的乳腺癌亚组与由转录谱和临床标准定义的肿瘤亚型显著相关（P < 0.000001）。在三个激素受体阳性的数据集中，在单变量和多变量分析中，细胞周期蛋白B1是与不良预后相关的主要细胞周期蛋白。尽管在基底样亚型与其他亚型相比，CCNE1的拷贝数显著更高（方差分析P < 0.001），但CCNB1基因拷贝数在乳腺癌中未显示增加。相反，在同时存在TP53突变和MYC扩增的肿瘤中细胞周期蛋白B1表达增加，这种组合似乎是基底样和腔面B型肿瘤的特征。CCNB1基因表达与PLK、CENPE和AURKB基因表达显著相关。
细胞周期蛋白B1、D1和E1在不同的乳腺癌亚型中有不同的表达。新型的PLK、CENPE和AURKB抑制剂应在细胞周期蛋白B1过度表达且预后不良的乳腺癌中评估其治疗效用。
We studied the expression levels of cyclins B1, D1, and E1 and the implications of cyclin overexpression for patient outcomes in distinct breast cancer subtypes defined by clinical variables and transcriptional profiling. The expression levels of cyclins B1, D1, and E1 were quantified in 779 breast tumors and 53 cell lines using reverse phase protein arrays and/or transcriptional profiling. Whereas cyclin E1 overexpression was a specific marker of triple-negative and basal-like tumors, cyclin B1 overexpression occurred in poor prognosis hormone receptor–positive, luminal B and basal-like breast cancers. Cyclin D1 overexpression occurred in luminal and normal-like cancers. Breast cancer subgroups defined by integrated expression of cyclins B1, D1, and E1 correlated significantly (P < 0.000001) with tumor subtypes defined by transcriptional profiling and clinical criteria. Across three hormone receptor–positive data sets, cyclin B1 was the dominant cyclin associated with poor prognosis in univariate and multivariate analyses. Although CCNE1 was present in significantly higher copy numbers in basal-like versus other subtypes (ANOVA P < 0.001), CCNB1 gene copy number did not show gain in breast cancer. Instead, cyclin B1 expression was increased in tumors with co-occurrence of TP53 mutations and MYC amplification, a combination that seems to characterize basal-like and luminal B tumors. CCNB1 gene expression was significantly correlated with PLK, CENPE, and AURKB gene expression. Cyclins B1, D1, and E1 have distinct expressions in different breast cancer subtypes. Novel PLK, CENPE, and AURKB inhibitors should be assessed for therapeutic utility in poor prognosis cyclin B1–overexpressing breast cancers.