乳腺组织中microRNA的异常表达与乳腺癌的发生密切相关

    生物中国人报道：本月位于莱斯布里奇大学的科研人员以大鼠为模型利用microRNA表达谱分析、表观基因组学以及蛋白组学方法对乳腺癌的发病表征进行了最新阐释（O. Kovalchuk, etal. Estrogen-Induced Rat Breast Carcinogenesis is Characterized by Alterations in DNA Methylation, Histone Modifications and Aberrant MicroRNA Expression. Cell Cycle 6:16, 2010-2018）。

    此项研究的最大成果是首次论证了乳腺组织中miRNA的表达与DNA甲基化和组蛋白甲基化形态变化中表现出的表观遗传失调密切相关。特别是使用miRNA微阵列（由LC Sciences提供）对E2诱导产生的大鼠癌症发生过程进行分析，发现miR-22，miR-99a，miR-99b以及miR-127出现下调，并且显示这些下调的miRNAs与目标致癌基因的活动加剧有关。通过一系列深入的研究，研究人员得出以下结论：DNA以及组蛋白的甲基化变化，更为重要的是，miRNA组的异常可能会导致出现具有肿瘤特异性表型的表观遗传基因程序重组细胞，而这些细胞日后将引起恶性转化。

Abstract

Breast cancer is the most common malignancy in women continuing to rise worldwide. Breast cancer emerges through a multi‑step process, encompassing progressive changes from a normal cell to hyperplasia (with and without atypia), carcinoma in situ, invasive carcinoma, and metastasis. In the current study, we analyzed the morphological changes and alterations of DNA methylation, histone methylation and microRNA expression during estradiol‑17b (E2)‑induced mammary carcinogenesis in female August Copenhagen Irish (ACI) rats. E2‑induced breast carcinogenesis in ACI rats provides a physiologically relevant and genetically defined animal model for studying human sporadic breast cancer. The pattern of morphological changes in mammary glands during E2‑induced carcinogenesis was characterized by transition from normal appearing alveolar and ductular hyper­plasia to focal hyperplastic areas of atypical glands and ducts accompanied by a rapid and sustained loss of global DNA methylation, LINE‑1 hypomethylation, loss of histone H3 lysine 9 and histone H4 lysine 20 trimethylation, and altered microRNAs expression. More importantly, these alterations in the mammary tissue occurred after six weeks of E2‑treatment, whereas the atypical hyperplasia, which represents a putative precursor lesion to mammary carcinoma in this model, was detected only after twelve weeks of exposure, demonstrating clearly that these events are directly associated with the effects of E2 and are not a consequence of the preexisting preneoplastic lesions. The results of this study show that deregulation of cellular epigenetic processes plays a crucial role in the mechanism of E2‑induced mammary carcinogenesis in ACI rats, especially in the tumor initiation process.

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Estrogen-Induced Rat Breast Carcinogenesis is Characterized by Alterations in DNA Methylation, Histone Modifications and Aberrant MicroRNA Expression.