Abstract 288: TGF-beta induced epithelial-to-mesenchymal transition is attenuated when the MNK/eIF4E pathway is functionally impaired.

Abstract

Abstract The epithelial-mesenchymal-like transition (EMT) is a process enabling epithelial cells to gain the motile characteristics of mesenchymal cells, in a manner resembling metastasis. TGF-beta, via well-defined transcriptional mechanisms, is considered a master regulator of EMT. However, the idea that TGF-beta can regulate the translational machinery to drive EMT remains largely unexplored. The eukaryotic translation initiation factor eIF4E is known to be overexpressed in breast cancer, has been linked to increased invasiveness, and is a promising target for the treatment of breast cancer. Our hypothesis is that phosphorylation of eIF4E stimulated by TGF-beta is required for inducing EMT and metastasis in breast cancer. Our novel preliminary data show that TGF-beta can stimulate eIF4E phosphorylation as normal mammary epithelial cells become mesenchymal. Silencing of eIF4E attenuates molecular and behavioral changes associated with EMT. Moreover, decreasing eIF4E levels can impair TGF-beta induced migration and invasion of ErbB2-expressing breast cancer cells. In keeping with a role of phosphorylated eIF4E in driving the metastatic phenotype, we show that chemically and genetically inhibiting the eIF4E kinase MNK1 attenuates TGF-beta-stimulated EMT. We hypothesized that the expression of master regulators of EMT could be restricted when the eIF4E/MNK pathway is functionally impaired, which prompted us to look at the expression of Twist and Snail in TGF-beta treated eIF4E- and MNK- silenced cells. Our data shows that TGF-beta-induced Snail protein expression, but not mRNA level, is repressed when the MNK/eIF4E pathway is functionally impaired. Our results indicate that MNK and eIF4E are essential for EMT and suggest that therapeutic inhibition of MNK/eIF4E pathway may be a useful strategy for the control of tumor invasion and metastasis. Citation Format: Sonia V. del Rincon, Bonnie Huor, Elaine Ngan, Luca Petruccelli, Peter Siegel, Wilson H. Miller, Jr. TGF-beta induced epithelial-to-mesenchymal transition is attenuated when the MNK/eIF4E pathway is functionally impaired. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 288. doi:10.1158/1538-7445.AM2013-288