DNA methylation changes in murine breast adenocarcinomas allow the identification of candidate genes for human breast carcinogenesis
DNA methylation changes in murine breast adenocarcinomas allow the identification of candidate genes for human breast carcinogenesis
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DOI：
10.1007/s00335-011-9318-6
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发表时间：
2011-04-01
期刊：
影响因子：
2.5
通讯作者：
Montagna, Cristina
中科院分区：
文献类型：
--
作者：
Acosta, Deanna;Suzuki, Masako;Montagna, Cristina
由于异常启动子甲基化导致的表观遗传失活是乳腺肿瘤发生的关键过程。几乎所有重要的癌基因或抑癌基因都建立了小鼠乳腺癌模型。小鼠到人类的比较基因表达和细胞遗传学分析已被广泛研究，这些模型，然而，鲜为人知的是保守的表观遗传学改变在肿瘤发生。为了确定人类乳腺肿瘤发生中的这一关键过程是否也反映在小鼠乳腺癌模型中，我们绘制了来自多瘤病毒中T抗原小鼠模型的原发性腺癌和配对肺转移中的胞嘧啶甲基化变化。与正常乳腺相比，在所有肿瘤中观察到甲基胞嘧啶水平的总体变化。观察到Hoxa7（一种在人类乳腺肿瘤中差异甲基化的基因）和Gata2（一种新的候选基因）的异常甲基化和相关基因沉默。对人原发性肿瘤库中HOXA 7和GATA 2表达的分析证实，这些基因的表达在人乳腺癌中也降低。此外，与邻近的无肿瘤组织相比，在乳腺癌组织中观察到HOXA 7超甲基化。基于这些研究，我们提出了一个模型，其中比较表观遗传学技术可用于识别新的候选基因的重要人类乳腺肿瘤的发生，在原发性和转移性肿瘤。
Epigenetic inactivation due to aberrant promoter methylation is a key process in breast tumorigenesis. Murine models for human breast cancer have been established for nearly every important human oncogene or tumor suppressor gene. Mouse-to-human comparative gene expression and cytogenetic profiling have been widely investigated for these models; however, little is known about the conservation of epigenetic alterations during tumorigenesis. To determine if this key process in human breast tumorigenesis is also mirrored in a murine breast cancer model, we mapped cytosine methylation changes in primary adenocarcinomas and paired lung metastases derived from the polyomavirus middle T antigen mouse model. Global changes in methylcytosine levels were observed in all tumors when compared to the normal mammary gland. Aberrant methylation and associated gene silencing was observed for Hoxa7, a gene that is differentially methylated in human breast tumors, and Gata2, a novel candidate gene. Analysis of HOXA7 and GATA2 expression in a bank of human primary tumors confirms that the expression of these genes is also reduced in human breast cancer. In addition, HOXA7 hypermethylation is observed in breast cancer tissues when compared to adjacent tumor-free tissue. Based on these studies, we present a model in which comparative epigenetic techniques can be used to identify novel candidate genes important for human breast tumorigenesis, in both primary and metastatic tumors.