The p52 isoform of SHC1 is a key driver of breast cancer initiation
The p52 isoform of SHC1 is a key driver of breast cancer initiation
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DOI：
10.1186/s13058-019-1155-7
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发表时间：
2019-06-15
影响因子：
7.4
通讯作者：
Sorokin, Andrey
中科院分区：
文献类型：
--
作者：
Wright, Kevin D.;Miller, Bradley S.;Sorokin, Andrey
背景SHC 1蛋白（也称为SHCA）存在于三种功能不同的亚型（p46 SHC、p52 SHC和p66 SHC）中，它们在乳腺癌中充当几种关键信号通路的细胞内衔接子。尽管有广泛的证据表明SHC 1基因产物作为乳腺癌的中央介质，测试的亚型特异性作用的SHC 1蛋白已无法访问，由于缺乏亚型特异性抑制剂或基因敲除models.MethodsHere，我们解决了这个问题，通过生成第一个亚型特异性基因敲除模型p52 SHC和p66 SHC，使用生殖系基因编辑在盐敏感的大鼠品系。与野生型（WT）大鼠相比，我们发现，基因消融的p52 SHC亚型显着衰减乳腺肿瘤的形成，而p66 SHC敲除没有影响。用7，12-二甲基苯并蒽（DMBA）经口灌胃诱发大鼠乳腺肿瘤，观察15周的肿瘤进展。结果与野生型（WT）大鼠相比，p52 SHC基因敲除组大鼠乳腺肿瘤形成明显减少，而p66 SHC基因敲除组大鼠乳腺肿瘤形成无明显变化。这些数据，结合p52 SHC是在人类和大鼠肿瘤中上调的主要亚型，提供了第一个证据，即p52 SHC是乳腺癌中Shc 1基因产物的致癌亚型。与WT肿瘤相比，893例差异表达（DE; FDR
BackgroundSHC1 proteins (also called SHCA) exist in three functionally distinct isoforms (p46SHC, p52SHC, and p66SHC) that serve as intracellular adaptors for several key signaling pathways in breast cancer. Despite the broad evidence implicating SHC1 gene products as a central mediator of breast cancer, testing the isoform-specific roles of SHC1 proteins have been inaccessible due to the lack of isoform-specific inhibitors or gene knockout models.MethodsHere, we addressed this issue by generating the first isoform-specific gene knockout models for p52SHC and p66SHC, using germline gene editing in the salt-sensitive rat strain. Compared with the wild-type (WT) rats, we found that genetic ablation of the p52SHC isoform significantly attenuated mammary tumor formation, whereas the p66SHC knockout had no effect. Rats were dosed with 7,12-dimethylbenz(a)anthracene (DMBA) by oral gavage to induce mammary tumors, and progression of tumor development was followed for 15weeks. At 15weeks, tumors were excised and analyzed by RNA-seq to determine differences between tumors lacking p66SHC or p52SHC.ResultsCompared with the wild-type (WT) rats, we found that genetic ablation of the p52SHC isoform significantly attenuated mammary tumor formation, whereas the p66SHC knockout had no effect. These data, combined with p52SHC being the predominant isoform that is upregulated in human and rat tumors, provide the first evidence that p52SHC is the oncogenic isoform of Shc1 gene products in breast cancer. Compared with WT tumors, 893 differentially expressed (DE; FDR