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EZH2和BMI1与乳腺癌的预后及TP53突变呈负相关。

EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer.

作者信息

Pietersen Alexandra M, Horlings Hugo M, Hauptmann Michael, Langerød Anita, Ajouaou Abderrahim, Cornelissen-Steijger Paulien, Wessels Lodewijk F, Jonkers Jos, van de Vijver Marc J, van Lohuizen Maarten

机构信息

Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066X, The Netherlands.

出版信息

Breast Cancer Res. 2008;10(6):R109. doi: 10.1186/bcr2214. Epub 2008 Dec 19.

DOI:10.1186/bcr2214
PMID:19099573
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2656906/
Abstract

INTRODUCTION

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.

METHODS

We have analysed the expression of EZH2 and BMI1 in a well-characterised dataset of 295 human breast cancer samples.

RESULTS

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.

CONCLUSIONS

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.

摘要

引言

多梳蛋白家族（PcG）通过组蛋白修饰维持基因抑制，并参与干细胞调控和癌症发生。EZH2是多梳抑制复合物2（PRC2）的一部分，可使H3K27发生三甲基化。这种组蛋白标记招募含BMI1的PRC1，从而使由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预后不良。

方法

我们分析了295例人类乳腺癌样本的特征明确的数据集中EZH2和BMI1的表达情况。

结果

有趣的是，虽然EZH2过表达与乳腺癌预后不良相关，但BMI1过表达与良好预后相关。尽管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。多梳蛋白家族靶向基因INK4A和ARF在BMI1高表达的肿瘤中不表达，但在EZH2过表达的肿瘤中表达。ARF表达导致肿瘤蛋白P53（TP53）激活，并且我们发现EZH2高表达的肿瘤中TP53突变比例显著更高。这可能解释了为什么与BMI1高表达的肿瘤相比，EZH2高表达的肿瘤对治疗反应较差。

结论

总体而言，我们的数据表明，虽然EZH2和BMI1在正常发育中可能以“线性”途径发挥作用，但它们的过表达对乳腺肿瘤发生具有不同的功能影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93f5/2656906/6e3ab0e2c4d3/bcr2214-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93f5/2656906/5a3ac5cd5d7e/bcr2214-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93f5/2656906/18e2615e2ccf/bcr2214-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93f5/2656906/8483b959d3e0/bcr2214-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93f5/2656906/af358f8918d1/bcr2214-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93f5/2656906/6e3ab0e2c4d3/bcr2214-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93f5/2656906/5a3ac5cd5d7e/bcr2214-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93f5/2656906/18e2615e2ccf/bcr2214-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93f5/2656906/8483b959d3e0/bcr2214-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93f5/2656906/af358f8918d1/bcr2214-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93f5/2656906/6e3ab0e2c4d3/bcr2214-5.jpg

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