Theodorou Vassiliki, Kimm Melanie A, Boer Mandy, Wessels Lodewyk, Theelen Wendy, Jonkers Jos, Hilkens John
Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Nat Genet. 2007 Jun;39(6):759-69. doi: 10.1038/ng2034. Epub 2007 Apr 29.
We performed a high-throughput retroviral insertional mutagenesis screen in mouse mammary tumor virus (MMTV)-induced mammary tumors and identified 33 common insertion sites, of which 17 genes were previously not known to be associated with mammary cancer and 13 had not previously been linked to cancer in general. Although members of the Wnt and fibroblast growth factors (Fgf) families were frequently tagged, our exhaustive screening for MMTV insertion sites uncovered a new repertoire of candidate breast cancer oncogenes. We validated one of these genes, Rspo3, as an oncogene by overexpression in a p53-deficient mammary epithelial cell line. The human orthologs of the candidate oncogenes were frequently deregulated in human breast cancers and associated with several tumor parameters. Computational analysis of all MMTV-tagged genes uncovered specific gene families not previously associated with cancer and showed a significant overrepresentation of protein domains and signaling pathways mainly associated with development and growth factor signaling. Comparison of all tagged genes in MMTV and Moloney murine leukemia virus-induced malignancies showed that both viruses target mostly different genes that act predominantly in distinct pathways.
我们在小鼠乳腺肿瘤病毒（MMTV）诱导的乳腺肿瘤中进行了高通量逆转录病毒插入诱变筛选，鉴定出33个常见插入位点，其中17个基因以前未知与乳腺癌相关，13个基因以前一般未与癌症相关联。尽管Wnt和成纤维细胞生长因子（Fgf）家族成员经常被标记，但我们对MMTV插入位点的详尽筛选发现了一系列新的候选乳腺癌致癌基因。我们通过在p53缺陷的乳腺上皮细胞系中过表达，验证了其中一个基因Rspo3是致癌基因。候选致癌基因的人类直系同源基因在人类乳腺癌中经常失调，并与几个肿瘤参数相关。对所有MMTV标记基因的计算分析发现了以前未与癌症相关的特定基因家族，并显示主要与发育和生长因子信号传导相关的蛋白质结构域和信号通路明显过度富集。比较MMTV和莫洛尼鼠白血病病毒诱导的恶性肿瘤中所有标记基因发现，两种病毒靶向的大多是不同的基因，这些基因主要在不同的途径中起作用。
