The epithelial-mesenchymal transition (EMT) is a developmental program that is aberrantly activated in cancer cells, producing an invasive phenotype that can lead to metastases. Inducers of EMT are largely known and have been widely studied. However, the mechanisms that regulate the link between extracellular stimuli and EMT phenotypes remain poorly understood. Preliminary evidence from our laboratory suggests that downregulation of proteasome activity may be responsible, in part, for driving EMT. Using immortalized human mammary epithelial (HMLE) cells as a model, we show that (1) EMT is associated with decreased proteasome activity and increased polyubiquitinated substrates, (2) pharmacologic inhibition of proteasome activity leads to increased EMT phenotypes and functionality, and (3) pharmacologic inhibition of proteasome activity leads to increased EMT via stabilization of the TGF-β signaling pathway. Together, these data suggest that proteasome activity may be an unappreciated regulator of EMT.

Citation Format: Daniel A. Garcia, Asoka Banno, Eric D. Van Baarsel, Patrick J. Metz, Christella E. Widjaja, Stephanie H. Kim, Jack D. Bui, Jing Yang, John T. Chang. Downregulation of proteasome activity promotes epithelial-mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1961. doi:10.1158/1538-7445.AM2017-1961