Agajanian Megan, Runa Farhana, Kelber Jonathan A
Department of Biology, California State University Northridge, Northridge, CA 91330, USA.
Department of Biology, California State University Northridge, Northridge, CA 91330, USA.
Biochem Biophys Res Commun. 2015 Sep 25;465(3):606-12. doi: 10.1016/j.bbrc.2015.08.071. Epub 2015 Aug 20.
Transforming Growth Factor beta (TGFβ) is the archetypal member of the TGFβ superfamily of ligands and has pleiotropic functions during normal development, adult tissue homeostasis and pathophysiological processes such as cancer. In epithelial cancers TGFβ signaling can either suppress tumor growth or promote metastasis via the induction of a well-characterized epithelial-mesenchymal transition (EMT) program. We recently reported that PEAK1 kinase mediates signaling cross talk between TGFβ receptors and integrin/Src/MAPK pathways and functions as a critical molecular regulator of TGFβ-induced breast cancer cell proliferation, migration, EMT and metastasis. Here, we examined the breast cancer cell contexts in which TGFβ induces both EMT and PEAK1, and discovered this event to be unique to oncogene-transformed mammary epithelial cells and triple-negative breast cancer cells. Using the Cancer BioPortal database, we identified PEAK1 co-expressors across multiple malignancies that are also common to the TGFβ response gene signature (TBRS). We then used the ScanSite database to identify predicted protein-protein binding partners of PEAK1 and the PEAK1-TBRS co-expressors. Analysis of the Cytoscape interactome and Babelomics-derived gene ontologies for a novel gene set including PEAK1, CRK, ZEB1, IL11 and COL4A1 enabled us to hypothesize that PEAK1 may be regulating TGFβ-induced EMT via its interaction with or regulation of these other genes. In this regard, we have demonstrated that PEAK1 is necessary for TGFβ to induce ZEB1-mediated EMT in the context of fibronectin/ITGB3 activation. These studies and future mechanistic studies will pave the way toward identifying the context in which TGFβ blockade may significantly improve breast cancer patient outcomes.
转化生长因子β（TGFβ）是TGFβ配体超家族的原型成员，在正常发育、成人组织稳态以及癌症等病理生理过程中具有多效性功能。在上皮性癌症中，TGFβ信号传导既可以通过诱导一个特征明确的上皮-间质转化（EMT）程序来抑制肿瘤生长，也可以促进转移。我们最近报道，PEAK1激酶介导TGFβ受体与整合素/Src/丝裂原活化蛋白激酶（MAPK）途径之间的信号串扰，并作为TGFβ诱导的乳腺癌细胞增殖、迁移、EMT和转移的关键分子调节因子发挥作用。在此，我们研究了TGFβ诱导EMT和PEAK1的乳腺癌细胞环境，发现这一事件在癌基因转化的乳腺上皮细胞和三阴性乳腺癌细胞中是独特的。利用癌症生物信息数据库，我们在多种恶性肿瘤中鉴定出了也是TGFβ反应基因特征（TBRS）共表达的PEAK1共表达因子。然后，我们使用ScanSite数据库来鉴定PEAK1以及PEAK1-TBRS共表达因子的预测蛋白质-蛋白质结合伙伴。对包括PEAK1、CRK、ZEB1、IL11和COL4A1在内的一个新基因集的Cytoscape相互作用组和Babelomics衍生的基因本体进行分析，使我们能够假设PEAK1可能通过与这些其他基因相互作用或对其进行调节来调控TGFβ诱导的EMT。在这方面，我们已经证明，在纤连蛋白/整合素β3（ITGB3）激活的情况下，PEAK1是TGFβ诱导ZEB1介导的EMT所必需的。这些研究以及未来的机制研究将为确定TGFβ阻断可能显著改善乳腺癌患者预后的环境铺平道路。
