Abstract
The epithelial-mesenchymal transition (EMT) endows carcinoma cells with phenotypic plasticity that can facilitate the formation of cancer stem cells (CSCs) and contribute to the metastatic cascade. While there is substantial support for the role of EMT in driving cancer cell dissemination, less is known about the intracellular molecular mechanisms that govern formation of CSCs via EMT. Here we show that β2 and β5 proteasome subunit activity is downregulated during EMT in immortalized human mammary epithelial cells. Moreover, selective proteasome inhibition enabled mammary epithelial cells to acquire certain morphologic and functional characteristics reminiscent of cancer stem cells, including CD44 expression, self-renewal, and tumor formation. Transcriptomic analyses suggested that proteasome-inhibited cells share gene expression signatures with cells that have undergone EMT, in part, through modulation of the TGF-β signaling pathway. These findings suggest that selective downregulation of proteasome activity in mammary epithelial cells can initiate the EMT program and acquisition of a cancer stem cell-like phenotype. As proteasome inhibitors become increasingly used in cancer treatment, our findings highlight a potential risk of these therapeutic strategies and suggest a possible mechanism by which carcinoma cells may escape from proteasome inhibitor-based therapy.
Highlights
Cancer is one of the leading causes of death in the United States, and up to 90% of cancer-associated mortality can be attributed to therapy-resistant metastatic disease [1]
We utilized human mammary epithelial cells (HMLE) cells in which epithelial-mesenchymal transition (EMT) can be induced by stable overexpression of SNAI1 or TWIST1, or by treatment with TGF-β1, as previously described [6, 18,19,20,21,22]
We found that epithelial cells decrease their proteasome activity during EMT and that proteasome inhibitors can induce EMT
Summary
Cancer is one of the leading causes of death in the United States, and up to 90% of cancer-associated mortality can be attributed to therapy-resistant metastatic disease [1]. Tumor cells gain the capacity to invade locally and disseminate into the vasculature. Not all cells that enter the vasculature go on to colonize distant sites. A small subset of invading tumor cells acquire characteristics of cancer stem cells (CSCs) needed to establish macrometastases, namely self-renewal capacity, proliferative potential, and chemoresistance [2]. Previous studies have identified the transcription factors TWIST1, SNAI1, and ZEB1 as key inducers of EMT, metastasis, and the CSC phenotype [3, 6, 8,9,10]. Identifying the factors that regulate EMT is highly relevant to cancer therapy as these stimuli can be targeted to block metastasis, and potentially CSC formation, in carcinomas
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
