HER2/Neu tumorigenesis and metastasis is regulated by E2F activator transcription factors.
HER2/Neu tumorigenesis and metastasis is regulated by E2F activator transcription factors.
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作者：
HER2 / Neu在很大比例的人类乳腺癌中被扩增和过表达，但促进肿瘤发生和转移进展的信号通路尚不完全清楚。利用基因表达数据和通路特征，我们预测了激活子E2F转录因子在新诱导肿瘤中的作用。这是通过与敲除三种激活因子e2f的新转基因杂交进行的遗传测试。E2F的缺失延迟了Neu诱导的肿瘤发生。E2F1的缺失加速了肿瘤的生长，而E2F2和E2F3的缺失则没有。引人注目的是，我们观察到E2F1或E2F2的缺失显著降低了肿瘤的转移能力，这与E2F2敲除后循环肿瘤细胞的减少有关。不同E2F突变背景的肿瘤之间的基因表达分析显示，其他E2F家族成员在个体敲除中有广泛的补偿，强调了E2F在HER2 / Neu诱导肿瘤中的重要性。扩展到HER2阳性的人乳腺癌，发现基于E2F活性的许多HER2+亚型在无复发生存时间上存在差异。综上所述，这些数据表明E2F转录因子在HER2+肿瘤的发生和进展中是不可或缺的。
HER2 / Neu is amplified and overexpressed in a large proportion of human breast cancers, but the signaling pathways that contribute to tumor development and metastatic progression are not completely understood. Using gene expression data and pathway signatures we predicted a role for activator E2F transcription factors in Neu induced tumors. This was genetically tested by interbreeding Neu transgenics with knockouts of the three activator E2Fs. Loss of any E2F delayed Neu induced tumor onset. E2F1 loss accelerated tumor growth while E2F2 and E2F3 loss did not. Strikingly, it was observed that loss of E2F1 or E2F2 significantly reduced the metastatic capacity of the tumor and this was associated with a reduction in circulating tumor cells in the E2F2 knockout. Gene expression analysis between the tumors in the various E2F mutant backgrounds revealed that there was extensive compensation by other E2F family members in the individual knockouts, underscoring the importance of the E2Fs in HER2 / Neu induced tumors. Extension to HER2 positive human breast cancer revealed a number of HER2+ subtypes based on E2F activity with differences in relapse free survival times. Taken together these data demonstrate that the E2F transcription factors are integral to HER2+ tumor development and progression.
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DOI：
10.1073/pnas.0912708107
发表时间：
2010-04-13
影响因子：
11.1
作者：
Gatza, Michael L.;Lucas, Joseph E.;Nevins, Joseph R.
通讯作者：
Nevins, Joseph R.
影响因子：
16
作者：
Leone, G;Sears, R;Nevins, JR
通讯作者：
Nevins, JR
影响因子：
11.2
作者：
Fujiwara, Kenichiro;Yuwanita, Inez;Andrechek, Eran R.
通讯作者：
Andrechek, Eran R.
影响因子：
64.5
作者：
Kim, Jonghwan;Chu, Jianlin;Orkin, Stuart H.
通讯作者：
Orkin, Stuart H.
影响因子：
64.5
作者：
Field, SJ;Tsai, FY;Greenberg, ME
通讯作者：
Greenberg, ME