Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets.
Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets.
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DOI：
10.1038/onc.2009.489
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发表时间：
2010-04-08
期刊：
影响因子：
8
通讯作者：
Reis-Filho, J. S.
中科院分区：
文献类型：
--
作者：
Turner, N.;Lambros, M. B.;Horlings, H. M.;Pearson, A.;Sharpe, R.;Natrajan, R.;Geyer, F. C.;van Kouwenhove, M.;Kreike, B.;Mackay, A.;Ashworth, A.;de Vijver, M. J. van;Reis-Filho, J. S.
三阴性乳腺癌（tnbc）预后相对较差，目前的靶向治疗无法有效治疗。我们通过识别扩增时持续过度表达的基因来寻找有潜力成为治疗靶点的基因。对56个tnbc进行了高分辨率微阵列比较基因组杂交（aCGH），其中24个进行了全基因组基因表达分析。tnbc具有遗传异质性；尽管78.6%的tnbc至少有一个病灶放大，但在高频情况下没有单独的病灶放大。整合aCGH和表达数据显示，扩增后有40个基因显著过表达，包括已知的致癌基因和潜在的治疗靶点，FGFR2 （10q26.3）、BUB3 （10q26.3）、RAB20 （13q34）、PKN1 （19p13.12）和NOTCH3 （19p13.12）。我们鉴定了两种具有FGFR2扩增的TNBC细胞系，它们都具有FGFR2的组成性激活。扩增的细胞系对FGFR抑制剂PD173074和RNAi沉默FGFR2高度敏感。PD173074诱导细胞凋亡，部分原因是抑制了PI3K-AKT信号传导。使用公开可用的aCGH数据集进行的独立验证显示，FGFR2基因在4%（6/165）的TNBC中扩增，但在其他亚型中没有扩增（0/214,p=0.0065）。我们的分析表明tnbc是异质肿瘤，在肿瘤亚组中具有FGFR2扩增。
Triple negative breast cancers (TNBCs) have a relatively poor prognosis and cannot be effectively treated with current targeted therapies. We searched for genes that have the potential to be therapeutic targets by identifying genes consistently over-expressed when amplified. Fifty-six TNBCs were subjected to high-resolution microarray-based comparative genomic hybridisation (aCGH), of which 24 were subjected to genome-wide gene expression analysis. TNBCs were genetically heterogeneous; no individual focal amplification was present at high frequency, although 78.6% of TNBCs harboured at least one focal amplification. Integration of aCGH and expression data revealed 40 genes significantly overexpressed when amplified, including the known oncogenes and potential therapeutic targets, FGFR2 (10q26.3), BUB3 (10q26.3), RAB20 (13q34), PKN1 (19p13.12), and NOTCH3 (19p13.12). We identified two TNBC cell lines with FGFR2 amplification, which both had constitutive activation of FGFR2. Amplified cell lines were highly sensitive to FGFR inhibitor PD173074, and to RNAi silencing of FGFR2. Treatment with PD173074 induced apoptosis resulting partly from inhibition of PI3K-AKT signalling. Independent validation using publicly available aCGH datasets revealed FGFR2 gene was amplified in 4% (6/165) of TNBC, but not in other subtypes (0/214, p=0.0065). Our analysis demonstrates that TNBCs are heterogeneous tumours with amplifications of FGFR2 in a subgroup of tumours.
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DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
DOI：
10.1186/bcr1613
发表时间：
2006
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Hannemann J;Velds A;Halfwerk JB;Kreike B;Peterse JL;van de Vijver MJ
通讯作者：
van de Vijver MJ
影响因子：
11.5
作者：
Carey, Lisa A.;Dees, E. Claire;Perou, Charles M.
通讯作者：
Perou, Charles M.
影响因子：
7
作者：
Hicks, James;Krasnitz, Alexander;Zetterberg, Anders
通讯作者：
Zetterberg, Anders
影响因子：
5.7
作者：
Maira, Sauveur-Michel;Stauffer, Frederic;Garcia-Echeverria, Carlos
通讯作者：
Garcia-Echeverria, Carlos