EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer.
EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer.
复制标题
DOI：
10.1186/bcr2214
复制
发表时间：
2008
期刊：
影响因子：
--
通讯作者：
van Lohuizen M
中科院分区：
文献类型：
--
作者：
Pietersen AM;Horlings HM;Hauptmann M;Langerød A;Ajouaou A;Cornelissen-Steijger P;Wessels LF;Jonkers J;van de Vijver MJ;van Lohuizen M
PolycombGroup（PcG）蛋白通过组蛋白修饰维持基因抑制，并与干细胞调节和癌症有关。EZH2是Polycomb Repressive Complex 2（PRC2）的一部分，并使H3K27三甲基化。这种组蛋白标记募集含有BMI1的PRC1，PRC1使PRC2标记的基因沉默。基于它们在干细胞中的作用，EZH2和BMI1被预测会导致癌症患者的预后不良。我们分析了EZH2和BMI1在295个人类乳腺癌样本的充分表征的数据集中的表达。有趣的是，尽管EZH2过表达与乳腺癌的不良预后相关，但BMI1过表达与良好的预后相关。虽然这可能反映了不同细胞类型的转化，但我们也观察到了功能差异。PcG靶基因INK4A和ARF在具有高BMI 1的肿瘤中不表达，但它们在具有EZH2过表达的肿瘤中表达。ARF表达导致肿瘤蛋白P53（TP53）活化，我们发现在EZH2高的肿瘤中TP53突变的比例显著较高。这可能解释了为什么EZH2高的肿瘤对治疗反应不佳，而BMI1高的肿瘤则相反。总的来说，我们的数据强调，而EZH2和BMI1可能在正常发育中以“线性”途径发挥作用，它们的过表达对乳腺肿瘤发生具有不同的功能后果。
PolycombGroup (PcG) proteins maintain gene repression through histone modifications and have been implicated in stem cell regulation and cancer. EZH2 is part of Polycomb Repressive Complex 2 (PRC2) and trimethylates H3K27. This histone mark recruits the BMI1-containing PRC1 that silences the genes marked by PRC2. Based on their role in stem cells, EZH2 and BMI1 have been predicted to contribute to a poor outcome for cancer patients. We have analysed the expression of EZH2 and BMI1 in a well-characterised dataset of 295 human breast cancer samples. Interestingly, although EZH2 overexpression correlates with a poor prognosis in breast cancer, BMI1 overexpression correlates with a good outcome. Although this may reflect transformation of different cell types, we also observed a functional difference. The PcG-target genes INK4A and ARF are not expressed in tumours with high BMI1, but they are expressed in tumours with EZH2 overexpression. ARF expression results in tumour protein P53 (TP53) activation, and we found a significantly higher proportion of TP53 mutations in tumours with high EZH2. This may explain why tumours with high EZH2 respond poorly to therapy, in contrast to tumours with high BMI1. Overall, our data highlight that whereas EZH2 and BMI1 may function in a 'linear' pathway in normal development, their overexpression has different functional consequences for breast tumourigenesis.
登录
查看更多内容
影响因子：
5.3
作者：
O'Carroll, D;Erhardt, S;Jenuwein, T
通讯作者：
Jenuwein, T
DOI：
10.1186/bcr1734
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Duss S;André S;Nicoulaz AL;Fiche M;Bonnefoi H;Brisken C;Iggo RD
通讯作者：
Iggo RD
影响因子：
64.8
作者：
Efeyan, Alejo;Garcia-Cao, Isabel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
4.4
作者：
Hu, Zhiyuan;Fan, Cheng;Perou, Charles M.
通讯作者：
Perou, Charles M.
影响因子：
46.9
作者：
Hughes, TR;Mao, M;Linsley, PS
通讯作者：
Linsley, PS