乳腺癌的转录因子锌指突变特征

水面曲线乳腺癌的转录因子锌指突变特征

甲乙酮信息产业部手机查询编者按：转录因子GATA3的锌指结构能够与特定基因上游特定核苷酸序列（GATA）结合，从而调控遗传信息由DNA转录至RNA的过程。GATA3编码基因突变常见于乳腺癌，其对疾病过程或其乳腺癌转录网络机制的影响尚不明确，但是大多数人推测这些突变可以引起功能缺失。

2018年3月13日，英国《自然》旗下《自然·通讯》发表美国国家卫生研究院（NIH）国家环境卫生科学研究所（NIEHS）和北卡罗来纳大学综合癌症中心的研究报告，探讨了与GATA3突变相关的乳腺癌分子学和临床特征。

该研究根据GATA3第二锌指（ZnFn2）突变乳腺癌患者独特的临床特征定义了一种新型分类方案。作者利用新一代基因编辑工具（CRISPR）相关蛋白Cas9核酸酶工程化的ZnFn2突变细胞系，发现GATA3第二锌指（ZnFn2）某个等位基因突变，引起该基因型亚组（包括孕激素受体）结合能力丧失和表达减少。其他位点与上皮→间质转化相关，结合能力增强与基因表达增加相关。

因此，这些结果表明，并非所有GATA3突变都相同，而且ZnFn2突变通过功能获得和丧失对乳腺癌产生影响，为孕激素受体阴性乳腺癌（包括三阴性乳腺癌）的新型靶向疗法奠定了基础。

Nat Commun. 2018 Mar 13;9(1):1059.蔡澜食材字典

颐和园教学设计

GATA3 zinc finger 2 mutations reprogram the breast cancer transcriptional network.

Motoki Takaku, Sara A. Grimm, John D. Roberts, Kaliopi Chrysovergis, Brian D. Bennett, Page Myers, Lalith Perera, Charles J. Tucker, Charles M. Perou, Paul A. Wade.

National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

GATA3 is frequently mutated in breast cancer; these mutations are widely presumed to be loss-of function despite a dearth of information regarding their effect on disease course or their mechanistic impact on the breast cancer transcriptional network. Here, we address molecular and clinical features associated with GATA3 mutations. A novel classification scheme defines distinct clinical features for patients bearing breast tumors with mutations in the second GATA3 zinc-finger (ZnFn2). An engineered ZnFn2 mutant cell line by CRISPR-Cas9 reveals that mutation of one allele of the GATA3 second zinc finger (ZnFn2) leads to loss of binding and decreased expression at a subset of genes, including Progesterone Receptor. At other loci, associated with epithelial to mesenchymal transition, gain of binding correlates with increased gene expression. These results demonstrate that not all GATA3 mutations are equivalent and that ZnFn2 mutations impact breast cancer through gain and loss-of function.

爱尔维修

DOI: 10.1038/s41467-018-03478-4

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