Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Nat Genet. 2017 Aug;49(8):1219-1230. doi: 10.1038/ng.3905. Epub 2017 Jun 26.
Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype and accounts for 8-14% of all cases. Although the majority of human ILCs are characterized by the functional loss of E-cadherin (encoded by CDH1), inactivation of Cdh1 does not predispose mice to develop mammary tumors, implying that mutations in additional genes are required for ILC formation in mice. To identify these genes, we performed an insertional mutagenesis screen using the Sleeping Beauty transposon system in mice with mammary-specific inactivation of Cdh1. These mice developed multiple independent mammary tumors of which the majority resembled human ILC in terms of morphology and gene expression. Recurrent and mutually exclusive transposon insertions were identified in Myh9, Ppp1r12a, Ppp1r12b and Trp53bp2, whose products have been implicated in the regulation of the actin cytoskeleton. Notably, MYH9, PPP1R12B and TP53BP2 were also frequently aberrated in human ILC, highlighting these genes as drivers of a novel oncogenic pathway underlying ILC development.
浸润性小叶癌（ILC）是第二常见的乳腺癌亚型，占所有病例的 8-14%。尽管大多数人类 ILC 的特征是 E-钙黏蛋白（由 CDH1 编码）的功能丧失，但 Cdh1 的失活并不会使小鼠易于发生乳腺肿瘤，这意味着在小鼠中形成 ILC 需要其他基因突变。为了鉴定这些基因，我们使用睡眠美人转座子系统在乳腺特异性 Cdh1 失活的小鼠中进行了插入诱变筛选。这些小鼠发展出了多个独立的乳腺肿瘤，其中大多数在形态和基因表达上与人类 ILC 相似。在 Myh9、Ppp1r12a、Ppp1r12b 和 Trp53bp2 中发现了反复出现且相互排斥的转座子插入，这些基因的产物与肌动蛋白细胞骨架的调节有关。值得注意的是，MYH9、PPP1R12B 和 TP53BP2 在人类 ILC 中也经常发生异常，突出了这些基因作为 ILC 发展背后新型致癌途径的驱动因素。
