EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-catenin signaling.
EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-catenin signaling.
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DOI：
10.1016/j.ccr.2010.10.035
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发表时间：
2011-01-18
期刊：
影响因子：
50.3
通讯作者：
Hung MC
中科院分区：
文献类型：
--
作者：
Chang CJ;Yang JY;Xia W;Chen CT;Xie X;Chao CH;Woodward WA;Hsu JM;Hortobagyi GN;Hung MC
已经提出，侵袭性继发性癌症干细胞群体通过获得额外的基因突变从原发性癌症干细胞群体产生，并驱动癌症进展。Polycomb蛋白EZH 2的过表达，在干细胞自我更新中必不可少，与乳腺癌进展有关。然而，将EZH 2表达增加与BTIC（乳腺肿瘤起始细胞）调节和癌症进展联系起来的关键机制仍不清楚。在这里，我们确定了一种机制，其中EZH 2表达介导的DNA损伤修复下调导致BTIC中复发性RAF 1基因扩增的积累，其激活p-ERK-β-catenin信号传导以促进BTIC扩增。我们进一步揭示了AZD 6244，一种抑制RAF 1-ERK信号传导的临床试验药物，可以通过消除BTIC来预防乳腺癌进展。
It has been proposed that an aggressive secondary cancer stem cell population arises from a primary cancer stem cell population through acquisition of additional genetic mutations and drives cancer progression. Overexpression of Polycomb protein EZH2, essential in stem cell self-renewal, has been linked to breast cancer progression. However, critical mechanism linking increased EZH2 expression to BTIC (breast tumor initiating cell) regulation and cancer progression remains unclear. Here, we identify a mechanism in which EZH2 expression-mediated downregulation of DNA damage repair leads to accumulation of recurrent RAF1 gene amplification in BTICs, which activates p-ERK-β-catenin signaling to promote BTIC expansion. We further reveal that AZD6244, a clinical trial drug that inhibits RAF1-ERK signaling, could prevent breast cancer progression by eliminating BTICs.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
6.5
作者：
Konopleva, M;Zhao, SR;Andreeff, M
通讯作者：
Andreeff, M
影响因子：
5.3
作者：
Bindra, RS;Schaffer, PJ;Glazer, PM
通讯作者：
Glazer, PM
影响因子：
64.5
作者：
FORD, M;FRIED, M
通讯作者：
FRIED, M
DOI：
10.1073/pnas.0711613105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Liu, Suling;Ginestier, Christophe;Wicha, Max S.
通讯作者：
Wicha, Max S.