An In Vivo Gain-of-Function Screen Identifies the Williams-Beuren Syndrome Gene GTF2IRD1 as a Mammary Tumor Promoter.
An In Vivo Gain-of-Function Screen Identifies the Williams-Beuren Syndrome Gene GTF2IRD1 as a Mammary Tumor Promoter.
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DOI：
10.1016/j.celrep.2016.05.011
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发表时间：
2016-06-07
期刊：
影响因子：
8.8
通讯作者：
Macara IG
中科院分区：
文献类型：
--
作者：
Huo Y;Su T;Cai Q;Macara IG
由于缺乏肿瘤发生过程中涉及的基因的完整清单，精准医学在癌症中的广泛实施受到阻碍。我们利用MMTV-ErbB2原发乳腺组织中的慢病毒表达载体，在体内筛选了约1000个与乳腺癌信号相关的基因，这些基因在乳腺癌中具有积极作用。RET、GTF2IRD1、ADORA1、LARS2、DPP8等5个基因的功能获得显著促进乳腺肿瘤的生长。我们进一步研究了一个肿瘤促进基因，转录因子GTF2IRD1。GTF2IRD1下游基因（包括TβR2和BMPR1b）的错误调控也单独促进了乳腺癌的发展，TβR2的沉默抑制了GTF2IRD1驱动的肿瘤促进。此外，GTF2IRD1在人乳腺肿瘤中高表达，与肿瘤分级高、预后差相关。我们的体内方法很容易扩展到肿瘤促进基因的全基因组注释。
The broad implementation of precision medicine in cancer is impeded by the lack of a complete inventory of the genes involved in tumorigenesis. We screened in vivo ~1,000 genes, that are associated with signaling for positive roles in breast cancer, using lentiviral expression vectors in primary MMTV-ErbB2 mammary tissue. Gain-of-function of five genes, including RET, GTF2IRD1, ADORA1, LARS2, and DPP8 significantly promoted mammary tumor growth. We further studied one tumor promoting gene, the transcription factor GTF2IRD1. The misregulation of genes downstream of GTF2IRD1, including TβR2 and BMPR1b, also individually promoted mammary cancer development, and silencing of TβR2 suppressed GTF2IRD1-driven tumor promotion. In addition, GTF2IRD1 is highly expressed in human breast tumors, correlating with high tumor grades and poor prognosis. Our in vivo approach is readily expandable to whole genome annotation of tumor promoting genes.