Overexpression of HER2 signaling to WAVE2-Arp2/3 complex activates MMP-independent migration in breast cancer
Overexpression of HER2 signaling to WAVE2-Arp2/3 complex activates MMP-independent migration in breast cancer
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DOI：
10.1007/s10549-010-0896-x
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发表时间：
2011-04-01
影响因子：
3.8
通讯作者：
Mukai, Kiyoshi
中科院分区：
文献类型：
--
作者：
Yokotsuka, Mayumi;Iwaya, Keiichi;Mukai, Kiyoshi
触发板足形成并启动哺乳动物细胞定向迁移的最终信号是Wiskott-Aldrich综合征(WASP)/WASP家族超脯氨酸同源蛋白2 （WAVE2）与肌动蛋白相关蛋白2和3 （Arp2/3）复合物的结合。这种WAVE2-Arp2/3信号在一些乳腺癌中被认为是增强的，促进了浸润和/或转移。在这里，我们使用四种乳腺癌细胞系（SKBR3、AU565、MCF7和MDA-MB-231）证明了信号增强的一个原因。利用高功率共聚焦激光显微镜，通过计算同时表达WAVE2和Arp2的板足的数量，半定量地估计WAVE2-Arp2/3信号。WAVE2-Arp2/3信号在具有HER2基因扩增的SKBR3和AU565细胞系中的表达高于其他两种缺乏HER2基因扩增的细胞系。在Boyden实验中，曲妥珠单抗抑制SKBR3和AU565板足的形成和迁移。将HER2基因转染到MCF7后，板足细胞和迁移细胞的数量均增加。这种迁移的增强在细胞外基质的存在下没有发生，酶谱分析显示HER2基因转染的细胞和MCF7细胞之间没有明显的差异。115例乳腺癌的免疫组化分析显示，WAVE2和Arp2的共表达与her2过表达有显著相关性（P < 0.0001）。这些数据表明，由HER2基因扩增引起的异常信号激活了乳腺癌细胞的板足形成，从而启动了它们不依赖金属蛋白酶的迁移。
The final signal for triggering the formation of lamellipodia that initiate directional migration of mammalian cells is binding of the Wiskott-Aldrich syndrome (WASP)/WASP family verproline-homologous protein 2 (WAVE2) to the actin-related protein 2 and 3 (Arp2/3) complex. This WAVE2-Arp2/3 signal is suggested to be enhanced in some breast cancers, facilitating invasion, and/or metastasis. Here, we demonstrated one cause of the enhanced signal using four breast cancer cell lines (SKBR3, AU565, MCF7, and MDA-MB-231). The WAVE2-Arp2/3 signal was estimated semi-quantitatively by counting the number of lamellipodia expressing both WAVE2 and Arp2 using high-power confocal laser microscopy. Higher expression of the WAVE2-Arp2/3 signal was detected in SKBR3 and AU565, which have HER2 gene amplification, than in the other two cell lines that lack HER2 gene amplification. Trastuzumab suppressed both the formation of lamellipodia and migration in a Boyden chamber experiment in SKBR3 and AU565. When the HER2 gene was transfected into MCF7, the number of both lamellipodia and migrated cells was increased. This enhancement of migration did not occur in the presence of extracellular matrix, and zymographic analysis showed no clear difference between HER2 gene-transfected cells and MCF7 cells. Immunohistochemical analysis of 115 cases of breast cancer revealed that coexpression of WAVE2 and Arp2 was significantly correlated with HER2-overexpression (P < 0.0001). These data indicate that an abnormal signal resulting from HER2 gene amplification activates lamellipodia formation in breast cancer cells, which initiates their metalloproteinase-independent migration.