Epigenetic inactivation of BRCA1 is associated with aberrant expression of CTCF and DNA methyltransferase (DNMT3B) in some sporadic breast tumours
Epigenetic inactivation of BRCA1 is associated with aberrant expression of CTCF and DNA methyltransferase (DNMT3B) in some sporadic breast tumours
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DOI：
10.1016/j.ejca.2006.09.002
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发表时间：
2007-01-01
影响因子：
8.4
通讯作者：
Rodenhiser, David I.
中科院分区：
文献类型：
--
作者：
Butcher, Darci T.;Rodenhiser, David I.
我们评估了BRCA1、CTCF和DNMT3b甲基转移酶基因的表达以及BRCA1启动子甲基化，以更好地定义散发性乳腺癌中BRCA1失活相关的表观遗传事件。这些基因表达模式通过免疫组化在54例散发性乳腺肿瘤中确定，并使用甲基化特异性PCR评估BRCA1启动子的甲基化状态。我们在80%的肿瘤中观察到DNMT3b的显著表达，43%的肿瘤表现出新的细胞质CTCF表达。基因表达模式两两分析显示28/32的肿瘤；缺乏BRCA1表达，也表现出细胞质CTCF染色，而24/32的肿瘤也过表达DNMT3b。此外，86%的BRCA1低表达肿瘤在BRCA1启动子处甲基化，这些肿瘤的一个子集显示细胞质CTCF和DNMT3b表达增加。因此，存在BRCA1表达、BRCA1启动子甲基化、细胞质CTCF表达和DNMT3b过表达同时降低的肿瘤亚群。我们认为，这些改变的CTCF和DNMT3b表达模式代表(a)负责BRCA1表观遗传失活的关键事件和(b)散发性乳腺肿瘤中其他肿瘤抑制基因表观遗传失活的诊断特征。(c) 2006 Elsevier Ltd.版权所有。
We assessed expression of the BRCA1, CTCF and DNMT3b methyltransferase genes along with BRCA1 promoter methylation to better define the epigenetic events involved in BRCA1 inactivation in sporadic breast cancer. These gene expression patterns were determined in 54 sporadic breast tumours by immunohistochemistry and the methylation status of the BRCA1 promoter was evaluated using methylation-specific PCR. We observed significant DNMT3b expression in 80% of the tumours and that 43% of tumours exhibited novel cytoplasmic CTCF expression. Pairwise analyses of gene expression patterns showed that 28/32 tumours; lacked BRCA1 expression and also exhibited cytoplasmic CTCF staining, while 24/32 of these tumours also overexpressed DNMT3b. Furthermore, 86% of the BRCA1 low-expressing tumours were methylated at the BRCA1 promoter and a subset of these tumours displayed both cytoplasmic CTCF and increased DNMT3b expression. Thus, tumour subsets exist that display concurrent decreased BRCA1 expression, BRCA1 promoter methylation, cytoplasmic CTCF expression and with DNMT3b over-expression. We suggest that these altered CTCF and DNMT3b expression patterns represent (a) critical events responsible for the epigenetic inactivation of BRCA1 and (b) a diagnostic signature for epigenetic inactivation of other tumour suppressor genes in sporadic breast tumours. (c) 2006 Elsevier Ltd. All rights reserved.