Transducer of Cdc42-dependent actin assembly promotes breast cancer invasion and metastasis
Transducer of Cdc42-dependent actin assembly promotes breast cancer invasion and metastasis
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DOI：
10.1038/onc.2012.317
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发表时间：
2013-06-20
期刊：
影响因子：
8
通讯作者：
Craig, A. W. B.
中科院分区：
文献类型：
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作者：
Chander, H.;Truesdell, P.;Craig, A. W. B.
转移性乳腺腺癌显示触发细胞运动和组织侵袭的信号通路的激活特征。在这里，我们报告说，衔接蛋白转导Cdc 42依赖性肌动蛋白组装-1（Toca-1）在高度侵袭性乳腺癌中表达，并调节其转移表型。我们发现Toca-1定位于侵袭伪足突起的丝状肌动蛋白丰富核心，积极降解细胞外基质（ECM）。Toca-1与Corpine共定位，我们表明这种相互作用是由Toca-1的SH 3结构域介导的。Toca-1在MDA-MB-231细胞中表达的稳定敲减（KD）导致表皮生长因子（EGF）诱导的细胞迁移和侵袭显著缺陷。Toca-1 KD细胞在EGF和Src诱导的ECM消化和侵袭足膜突起形成方面也显示出显著缺陷。为了检测Toca-1在转移中的作用，我们在人和大鼠转移性乳腺癌细胞系中实现了稳定的Toca-1 KD。在自然杀伤/B-/T细胞缺陷小鼠中进行的对照和Toca-1 KD细胞原位肿瘤异种移植显示，在体内Toca-1沉默的情况下，自发性肺转移存在显著缺陷。相比之下，尾静脉注射Toca-1 KD细胞后未观察到原发性肿瘤生长或肺种植缺陷，表明Toca-1在转移性乳腺肿瘤细胞播散的早期发挥作用。综上所述，我们的结果确定Toca-1是乳腺癌中的促浸润蛋白，也是限制肿瘤转移的潜在治疗靶点。
Metastatic breast adenocarcinomas display activation signatures for signaling pathways that trigger cell motility and tissue invasion. Here, we report that the adaptor protein transducer of Cdc42-dependent actin assembly-1 (Toca-1) is expressed in highly invasive breast cancers and regulates their metastatic phenotypes. We show that Toca-1 localizes to the filamentous actin-rich core of invadopodial protrusions actively degrading the extracellular matrix (ECM). Toca-1 colocalizes with Cortactin, and we show that this interaction is mediated by the SH3 domain of Toca-1. Stable knockdown (KD) of Toca-1 expression in MDA-MB-231 cells led to a significant defect in epidermal growth factor (EGF)-induced cell migration and invasion. Toca-1 KD cells also showed significant defects in EGF- and Src-induced ECM digestion and formation of invadopodial membrane protrusions. To test the role of Toca-1 in metastasis, we achieved stable Toca-1 KD in both human and rat metastatic breast adenocarcinoma cell lines. Orthotopic tumor xenografting of control and Toca-1 KD cells in natural-killer /B-/T-cell-deficient mice revealed a significant defect in spontaneous lung metastases with Toca-1 silencing in vivo. In contrast, no defects in primary tumor growth or lung seeding following tail vein injection of Toca-1 KD cells was observed, suggesting that Toca-1 functions at an early step in the dissemination of metastatic breast tumor cells. Taken together, our results identify Toca-1 as a proinvasive protein in breast adenocarcinoma and a potential therapeutic target to limit tumor metastasis.