The Rho Exchange Factors Vav2 and Vav3 Control a Lung Metastasis-Specific Transcriptional Program in Breast Cancer Cells
The Rho Exchange Factors Vav2 and Vav3 Control a Lung Metastasis-Specific Transcriptional Program in Breast Cancer Cells
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DOI：
10.1126/scisignal.2002962
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发表时间：
2012-10-02
影响因子：
7.3
通讯作者：
Bustelo, Xose R.
中科院分区：
文献类型：
--
作者：
Citterio, Carmen;Menacho-Marquez, Mauricio;Bustelo, Xose R.
Rho和Rac亚家族的鸟苷三磷酸酶调节蛋白形成途径，并被鸟嘌呤核苷酸交换因子（Rho GEFs）激活，可能是抗癌治疗的潜在靶点。我们报道了两个Rho GEFs， Vav2和Vav3，通过维持肿瘤生长、新血管生成和许多涉及肺特异性转移的步骤，在乳腺癌中发挥协同作用。Vav蛋白在这些过程中的参与与Rac1和RhoA活性或细胞迁移无关，这意味着存在额外的生物学程序。微阵列分析显示，Vav2和Vav3通过两种蛋白共享的机制控制着乳腺癌细胞中大量的转录程序，这些机制是亚型特异性的或协同的。此外，vav调控转录本的丰度可通过rac1依赖性和rac1非依赖性途径进行调节。该转录组编码的治疗靶向蛋白在原发性肿瘤发生和肺特异性转移中发挥非冗多作用，如整合素连接激酶（Ilk）、转化生长因子- β家族配体抑制素β A、环氧化酶-2和上皮细胞粘附分子Tacstd2。它还包含预测乳腺癌患者疾病结果的基因特征。这些结果确定了治疗乳腺癌和肺转移的可能靶点，并为临床使用提供了潜在的诊断工具。
The guanosine triphosphatases of the Rho and Rac subfamilies regulate protumorigenic pathways and are activated by guanine nucleotide exchange factors (Rho GEFs), which could be potential targets for anticancer therapies. We report that two Rho GEFs, Vav2 and Vav3, play synergistic roles in breast cancer by sustaining tumor growth, neoangiogenesis, and many of the steps involved in lung-specific metastasis. The involvement of Vav proteins in these processes did not correlate with Rac1 and RhoA activity or cell migration, implying the presence of additional biological programs. Microarray analyses revealed that Vav2 and Vav3 controlled a vast transcriptional program in breast cancer cells through mechanisms that were shared between the two proteins, isoform-specific or synergistic. Furthermore, the abundance of Vav-regulated transcripts was modulated by Rac1-dependent and Rac1-independent pathways. This transcriptome encoded therapeutically targetable proteins that played nonredundant roles in primary tumorigenesis and lung-specific metastasis, such as integrin-linked kinase (Ilk), the transforming growth factor-beta family ligand inhibin beta A, cyclooxygenase-2, and the epithelial cell adhesion molecule Tacstd2. It also contained gene signatures that predicted disease outcome in breast cancer patients. These results identify possible targets for treating breast cancer and lung metastases and provide a potential diagnostic tool for clinical use.