GSK3β regulates epithelial-mesenchymal transition and cancer stem cell properties in triple-negative breast cancer

作者：Geraldine Vidhya Vijay, Na Zhao, Petra den Hollander, M J Toneff, Robiya Joseph, Mika Pietilä, Joseph H. Taube, Tapasree Roy Sarkar, Esmeralda Ramirez‐Peña, Steven J. Werden, Maryam Shariati, Ruli Gao, Mary M. Sobieski, CLIFFORD C. STEPHAN, Nathalie Sphyris, Noayuki Miura, Peter J. Davies, Jeffrey T. Chang, Rama Soundararajan, Jeffrey M. Rosen, Sendurai A. Mani · 发表于：Breast Cancer Research · 年份：2019 · DOI：10.1186/s13058-019-1125-0 · 被引用次数：175 · 研究领域：Cancer Cells and Metastasis、Wnt/β-catenin signaling in development and cancer、Hedgehog Signaling Pathway Studies

BACKGROUND: Triple-negative breast cancers (TNBCs), which lack receptors for estrogen, progesterone, and amplification of epidermal growth factor receptor 2, are highly aggressive. Consequently, patients diagnosed with TNBCs have reduced overall and disease-free survival rates compared to patients with other subtypes of breast cancer. TNBCs are characterized by the presence of cancer cells with mesenchymal properties, indicating that the epithelial to mesenchymal transition (EMT) plays a major role in the progression of this disease. The EMT program has also been implicated in chemoresistance, tumor recurrence, and induction of cancer stem cell (CSC) properties. Currently, there are no targeted therapies for TNBC, and hence, it is critical to identify the novel targets to treat TNBC. METHODS: A library of compounds was screened for their ability to inhibit EMT in cells with mesenchymal phenotype as assessed using the previously described Z-cad reporters. Of the several drugs tested, GSK3β inhibitors were identified as EMT inhibitors. The effects of GSK3β inhibitors on the properties of TNBC cells with a mesenchymal phenotype were assessed using qRT-PCR, flow cytometry, western blot, mammosphere, and migration and cell viability assays. Publicly available datasets also were analyzed to examine if the expression of GSK3β correlates with the overall survival of breast cancer patients. RESULTS: We identified a GSK3β inhibitor, BIO, in a drug screen as one of the most potent inhib...