Conserved E2F mediated metastasis in mouse models of breast cancer and HER2 positive patients.
Conserved E2F mediated metastasis in mouse models of breast cancer and HER2 positive patients.
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DOI：
10.18632/oncoscience.259
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Andrechek E
中科院分区：
文献类型：
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作者：
Rennhack J;Andrechek E
为了改善乳腺癌患者的预后，必须了解和阻断肿瘤转移。这项研究利用生物信息学技术和传统的遗传筛选，创造了一种新的方法来发现肿瘤进展的潜在贡献者，重点是肿瘤转移。使用先前定义的致癌活性特征，组装并查询来自各种乳腺癌小鼠模型的1172个表达数据的数据库。该分析揭示了MMTV-Neu小鼠模型中转录因子E2 F家族的高活性。MMTV-Neu小鼠与E2 F1缺失、E2 F2缺失或E2 F3杂合背景的遗传杂交显示肿瘤进展的显著变化，特别是肿瘤潜伏期和转移的减少以及E2 F1或E2 F2缺失。发现这些发现在人HER 2阳性患者中是保守的。E2 F1活性高的患者预后较差，如无复发生存期和无远处转移生存期。这项研究显示了人类乳腺癌亚型和类似小鼠模型中肿瘤进展的保守机制，并强调了增加对小鼠和人类肿瘤的表征和比较研究的重要性，以确定哪些小鼠模型类似于人类乳腺癌的每种亚型。
To improve breast cancer patient outcome work must be done to understand and block tumor metastasis. This study leverages bioinformatics techniques and traditional genetic screens to create a novel method of discovering potential contributors of tumor progression with a focus on tumor metastasis. A database of 1172 of expression data from a variety of mouse models of breast cancer was assembled and queried using previously defined oncogenic activity signatures. This analysis revealed high activity of the E2F family of transcription factors in the MMTV-Neu mouse model. A genetic cross of MMTV-Neu mice into an E2F1 null, E2F2 null, or E2F3 heterozygous background revealed significant changes in tumor progression specifically reductions in tumor latency and metastasis with E2F1 or E2F2 loss. These findings were found to be conserved in human HER2 positive patients. Patients with high E2F1 activity were shown to have worse outcomes such as relapse free survival and distant metastasis free survival. This study shows conserved mechanisms of tumor progression in human breast cancer subtypes and analogous mouse models and underlies the importance of increased research into the characterization of and comparisons between mouse and human tumors to identify which mouse models resemble each subtype of human breast cancer.