Department of Biomedicine, University of Basel, Basel, 4058, Switzerland.
Oncogene. 2018 Aug;37(31):4197-4213. doi: 10.1038/s41388-018-0270-8. Epub 2018 May 1.
An epithelial to mesenchymal transition (EMT) has been correlated to malignant tumor progression and metastasis by promoting cancer cell migration and invasion and chemoresistance. Hence, finding druggable EMT effectors is critical to efficiently interfere with metastasis formation and to overcome therapy resistance. We have employed a high-content microscopy screen in combination with a kinome and phosphatome-wide siRNA library to identify signaling pathways underlying an EMT of murine mammary epithelial cells and breast cancer cells. This screen identified the MEK5-ERK5 axis as a critical player in TGFβ-mediated EMT. Suppression of MEK5-ERK5 signaling completely prevented the morphological and molecular changes occurring during a TGFβ-induced EMT and, conversely, forced highly metastatic breast cancer cells into a differentiated epithelial state. Inhibition of MEK5-ERK5 signaling also repressed breast cancer cell migration and invasion and substantially reduced lung metastasis without affecting primary tumor growth. The results suggest that the MEK5-ERK5 signaling axis via activation of MEF2B and other transcription factors plays an important role in the induction and maintenance of breast cancer cell migration and invasion and thus represents an exploitable target for the pharmacological inhibition of cancer cell metastasis.
上皮间质转化 (EMT) 通过促进癌细胞迁移和侵袭以及化疗耐药性，与恶性肿瘤的进展和转移相关。因此，寻找可成药的 EMT 效应物对于有效地干扰转移形成和克服治疗耐药性至关重要。我们采用高内涵显微镜筛选结合激酶组和磷酸酶组的 siRNA 文库，鉴定了介导小鼠乳腺上皮细胞和乳腺癌细胞 EMT 的信号通路。该筛选确定了 MEK5-ERK5 轴在 TGFβ 介导的 EMT 中是一个关键的参与者。抑制 MEK5-ERK5 信号完全阻止了 TGFβ 诱导的 EMT 过程中发生的形态和分子变化，相反，将高度转移性的乳腺癌细胞强制转化为分化的上皮状态。抑制 MEK5-ERK5 信号还抑制了乳腺癌细胞的迁移和侵袭，并大大减少了肺转移，而不影响原发性肿瘤的生长。结果表明，MEK5-ERK5 信号轴通过激活 MEF2B 和其他转录因子，在诱导和维持乳腺癌细胞迁移和侵袭中发挥重要作用，因此代表了可用于抑制癌细胞转移的药理学靶点。
