The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion

From Springer Nature via Jisc Publications RouterHistory: received 2020-04-21, rev-recd 2021-03-23, accepted 2021-04-14, registration 2021-04-15, pub-electronic 2021-05-12, online 2021-05-12, pub-print 2021-06-10Publication status: PublishedFunder: Worldwide Cancer Research; doi: https://doi.org/10.13039/100011713; Grant(s): 15-1283Funder: RCUK | MRC | Medical Research Foundation; doi: https://doi.org/10.13039/501100009187; Grant(s): MC_PC_18056Abstract: There is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior

Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition

Matrix rigidity regulates a switch between TGF-β1–induced cell functions in two epithelial cell lines. On compliant polyacrylamide gels, TGF-β1 induced apoptosis, whereas on rigid gels, cells underwent an epithelial–mesenchymal transition (EMT). Compliant gels reduced PI3K/Akt activity, which was essential for cell survival and EMT on rigid gels

Distinct roles for paxillin and Hic-5 in regulating breast cancer cell morphology, invasion, and metastasis

This study reveals novel roles for the focal adhesion proteins paxillin and Hic-5 in regulating breast cancer invasion strategies and metastasis. Depletion of paxillin promotes a hypermesenchymal phenotype while dysregulating 3D adhesion dynamics. In contrast, RNAi of Hic-5 induces a hyperamoeboid phenotype with dysregulated RhoA/pMLC signaling