Cooperation between Pik3ca and p53 Mutations in Mouse Mammary Tumor Formation
Cooperation between Pik3ca and p53 Mutations in Mouse Mammary Tumor Formation
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DOI：
10.1158/0008-5472.can-10-0738
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发表时间：
2011-04-01
期刊：
影响因子：
11.2
通讯作者：
Egan, Sean E.
中科院分区：
文献类型：
--
作者：
Adams, Jessica R.;Xu, Keli;Egan, Sean E.
PIK 3CA编码磷脂酰肌醇3-激酶的p110 α催化亚基，是人类乳腺癌中最常见的突变基因之一。在这里，我们描述了一个小鼠模型PIK 3CA诱导的乳腺癌通过使用ROSA 26（R26）敲入系统，其中靶向Pik 3ca等位基因可以通过Cre重组酶的转基因表达激活。我们将Pik 3ca（H1047 R）和Pik 3ca（wt）敲入系与在乳腺上皮中表达Cre的MMTV-Cre转基因体交配。从约5月龄开始，雌性R26-Pik 3ca（H1047 R）;MMTV-Cre小鼠（但非对照R26-Pik 3ca（wt）;MMTV-Cre小鼠）发生乳腺肿瘤以及淋巴和皮肤恶性肿瘤。R26-Pik 3ca（H1047 R）;MMTV-Cre乳腺肿瘤通常为腺鳞癌或腺肌上皮瘤。由于p53是乳腺癌中最常见的突变基因，我们在R26-Pik 3ca（H1047 R）; p53（loxP/+）; MMTV-Cre小鼠中测试了Pik 3ca（H1047 R）和p53功能丧失突变之间的遗传相互作用。这导致双突变动物的存活率降低，这些动物以快速的动力学发展淋巴瘤和乳腺肿瘤。在p53（loxP/+）; MMTV-Cre条件突变体中形成的乳腺肿瘤是低分化腺癌或梭形细胞/EMT，而R26-Pik 3ca（H1047 R）; p53（loxP/+）; MMTV-Cre乳腺肿瘤主要是腺鳞癌或梭形细胞/EMT，表明双突变小鼠形成不同的乳腺肿瘤谱。因此，涉及多种人乳腺癌亚型的PIK 3CA的致癌变体可以在小鼠中诱导非常多样的乳腺肿瘤谱。此外，Pik 3ca（H1047 R）显示出与p53的合作，这改变了形成的特定肿瘤。因此，人类乳腺癌中最常突变的两个基因在乳腺肿瘤形成中表现出合作。Cancer Res; 71（7）; 2706-17.（C）2011年《非洲标准化评论》。
PIK3CA, which codes for the p110 alpha catalytic subunit of phosphatidylinositol 3-kinase, is one of the most frequently mutated genes in human breast cancer. Here, we describe a mouse model for PIK3CA-induced breast cancer by using the ROSA26 (R26) knock-in system, in which targeted Pik3ca alleles can be activated through transgenic expression of Cre recombinase. We mated Pik3ca(H1047R) and Pik3ca(wt) knock-in lines with MMTV-Cre transgenics, which express Cre in mammary epithelium. Starting at approximately 5 months of age, female R26-Pik3ca(H1047R);MMTV-Cre mice, but not control R26-Pik3ca(wt);MMTV-Cre mice, developed mammary tumors, as well as lymphoid and skin malignancies. R26-Pik3ca(H1047R);MMTV-Cre mammary tumors were typically either adenosquamous carcinoma or adenomyoepithelioma. As p53 is the most commonly mutated gene in breast cancer, we tested for genetic interaction between Pik3ca(H1047R) and p53 loss-of-function mutations in R26-Pik3ca(H1047R);p53(loxP/+); MMTV-Cre mice. This led to decreased survival of double-mutant animals, which developed lymphoma and mammary tumors with rapid kinetics. Mammary tumors that formed in p53(loxP/+); MMTV-Cre conditional mutants were either poorly differentiated adenocarcinoma or spindle cell/EMT, whereas R26-Pik3ca(H1047R); p53(loxP/+); MMTV-Cre mammary tumors were mostly adenosquamous carcinoma or spindle cell/EMT indicating that double-mutant mice develop a distinct spectrum of mammary tumors. Thus, an oncogenic variant of PIK3CA implicated in multiple human breast cancer subtypes can induce a very diverse spectrum of mammary tumors in mice. Furthermore, Pik3ca(H1047R) shows cooperation with p53, which altered the specific tumors that formed. Thus, the two most frequently mutated genes in human breast cancer show cooperation in mammary tumor formation. Cancer Res; 71(7); 2706-17. (C)2011 AACR.