Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Biol Chem. 2013 Jun 21;288(25):17954-67. doi: 10.1074/jbc.M113.475277. Epub 2013 May 7.
We previously established that overexpression of the EGF receptor (EGFR) is sufficient to induce tumor formation by otherwise nontransformed mammary epithelial cells, and that the initiation of epithelial-mesenchymal transition (EMT) is capable of increasing the invasion and metastasis of these cells. Using this breast cancer (BC) model, we find that in addition to EGF, adhesion to fibronectin (FN) activates signal transducer and activator of transcription 3 (STAT3) through EGFR-dependent and -independent mechanisms. Importantly, EMT facilitated a signaling switch from SRC-dependent EGFR:STAT3 signaling in pre-EMT cells to EGFR-independent FN:JAK2:STAT3 signaling in their post-EMT counterparts, thereby sensitizing these cells to JAK2 inhibition. Accordingly, human metastatic BC cells that failed to activate STAT3 downstream of EGFR did display robust STAT3 activity upon adhesion to FN. Furthermore, FN enhanced outgrowth in three-dimensional organotypic cultures via a mechanism that is dependent upon β1 integrin, Janus kinase 2 (JAK2), and STAT3 but not EGFR. Collectively, our data demonstrate that matrix-initiated signaling is sufficient to drive STAT3 activation, a reaction that is facilitated by EMT during BC metastatic progression.
我们之前已经证实，表皮生长因子受体（EGFR）的过度表达足以诱导原本非转化的乳腺上皮细胞形成肿瘤，而上皮-间充质转化（EMT）的启动能够增加这些细胞的侵袭和转移。使用这种乳腺癌（BC）模型，我们发现，除了 EGF 之外，黏附到纤维连接蛋白（FN）还能够通过 EGFR 依赖和独立的机制激活信号转导和转录激活因子 3（STAT3）。重要的是，EMT 促进了从 SRC 依赖的 EGFR：STAT3 信号到 EMT 后对应物中 EGFR 独立的 FN：JAK2：STAT3 信号的信号转换，从而使这些细胞对 JAK2 抑制敏感。因此，在黏附到 FN 时，未能激活 EGFR 下游 STAT3 的人转移性 BC 细胞确实显示出强大的 STAT3 活性。此外，FN 通过依赖于β1 整联蛋白、Janus 激酶 2（JAK2）和 STAT3 但不依赖于 EGFR 的机制增强了三维器官培养中的生长。总之，我们的数据表明，基质起始的信号足以驱动 STAT3 的激活，而 EMT 在 BC 转移进展过程中促进了这一反应。
