Prediction and Genetic Demonstration of a Role for Activator E2Fs in Myc-Induced Tumors
Prediction and Genetic Demonstration of a Role for Activator E2Fs in Myc-Induced Tumors
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DOI：
10.1158/0008-5472.can-10-2386
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发表时间：
2011-03-01
期刊：
影响因子：
11.2
通讯作者：
Andrechek, Eran R.
中科院分区：
文献类型：
--
作者：
Fujiwara, Kenichiro;Yuwanita, Inez;Andrechek, Eran R.
基因组特征的进展已经开始剖析乳腺癌的异质性，这些特征的应用将允许预测哪些途径在肿瘤发展中是重要的。在这里，我们使用基因组特征来预测Myc诱导的肿瘤中特异性E2 F转录因子的参与。我们通过将Myc转基因小鼠与缺乏各种激活因子E2 F等位基因的小鼠杂交，对这一预测进行了遗传学测试。肿瘤潜伏期在E2 F1突变体背景中减少，在E2 F2和E2 F3突变体中显著增加。研究这些变化背后的机制揭示了E2 F1敲除菌株中细胞凋亡的减少。E2 F2和E2 F3突变背景减轻了Myc对妊娠乳腺的增殖作用，减少了易感肿瘤靶群体。来自肿瘤的基因表达数据显示，E2 F2敲除背景导致较少的具有EMT的肿瘤，对应于Ras激活概率的降低。在人类乳腺癌中，我们发现E2 F2通路激活的低概率与无复发生存时间的增加相关。这些数据一起说明了基因组签名在破译乳腺癌内的异质性中的预测效用，并说明了在小鼠模型和人乳腺癌中介导肿瘤发生的个体E2 F的独特遗传要求。Cancer Res; 71（5）; 1924-32. (c)2011年AACR。
Advances in genomic signatures have begun to dissect breast cancer heterogeneity and application of these signatures will allow the prediction of which pathways are important in tumor development. Here we used genomic signatures to predict involvement of specific E2F transcription factors in Myc-induced tumors. We genetically tested this prediction by interbreeding Myc transgenics with mice lacking various activator E2F alleles. Tumor latency decreased in the E2F1 mutant background and significantly increased in both the E2F2 and E2F3 mutants. Investigating the mechanism behind these changes revealed a reduction in apoptosis in the E2F1 knockout strain. E2F2 and E2F3 mutant backgrounds alleviated Myc proliferative effects on the pregnant mammary gland, reducing the susceptible tumor target population. Gene expression data from tumors revealed that the E2F2 knockout background resulted in fewer tumors with EMT, corresponding with a reduction in probability of Ras activation. In human breast cancer we found that a low probability of E2F2 pathway activation was associated with increased relapse-free survival time. Together these data illustrate the predictive utility of genomic signatures in deciphering the heterogeneity within breast cancer and illustrate the unique genetic requirements for individual E2Fs in mediating tumorigenesis in both mouse models and human breast cancer. Cancer Res; 71(5); 1924-32. (c) 2011 AACR.