Snail-induced epithelial-to-mesenchymal transition of MCF-7 breast cancer cells: systems analysis of molecular changes and their effect on radiation and drug sensitivity

BMC Cancer

Research Article

Neda Jabbari¹  Lilya V. Matyunina¹  John F. McDonald¹  Roman Mezencev¹ 

[1] Integrated Cancer Research Center, School of Biology, and Parker H. Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, 315 Ferst Dr., 30332, Atlanta, GA, USA;

关键词: Epithelial-to-mesenchymal transition;    Snail;    Slug;    NF-κB;    Drug resistance;    Radiation sensitivity;    MCF-7;    Triple-negative breast-cancer;    Reactive oxygen species;    Glutathione;   

DOI  :  10.1186/s12885-016-2274-5

 received in 2015-04-16, accepted in 2016-03-13,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundEpithelial-to-mesenchymal transition (EMT) has been associated with the acquisition of metastatic potential and the resistance of cancer cells to therapeutic treatments. MCF-7 breast cancer cells engineered to constitutively express the zinc-finger transcriptional repressor gene Snail (MCF-7-Snail cells) have been previously shown to display morphological and molecular changes characteristic of EMT. We report here the results of a comprehensive systems level molecular analysis of changes in global patterns of gene expression and levels of glutathione and reactive oxygen species (ROS) in MCF-7-Snail cells and the consequence of these changes on the sensitivity of cells to radiation treatment and therapeutic drugs.MethodsSnail-induced changes in global patterns of gene expression were identified by microarray profiling using the Affymetrix platform (U133 Plus 2.0). The resulting data were processed and analyzed by a variety of system level analytical methods. Levels of ROS and glutathione (GSH) were determined by fluorescent and luminescence assays, and nuclear levels of NF-κB protein were determined by an ELISA based method. The sensitivity of cells to ionizing radiation and anticancer drugs was determined using a resazurin-based cell cytotoxicity assay.ResultsConstitutive ectopic expression of Snail in epithelial-like, luminal A-type MCF-7 cells induced significant changes in the expression of >7600 genes including gene and miRNA regulators of EMT. Mesenchymal-like MCF-7-Snail cells acquired molecular profiles characteristic of triple-negative, claudin-low breast cancer cells, and displayed increased sensitivity to radiation treatment, and increased, decreased or no change in sensitivity to a variety of anticancer drugs. Elevated ROS levels in MCF-7-Snail cells were unexpectedly not positively correlated with NF-κB activity.ConclusionsEctopic expression of Snail in MCF-7 cells resulted in morphological and molecular changes previously associated with EMT. The results underscore the complexity and cell-type dependent nature of the EMT process and indicate that EMT is not necessarily predictive of decreased resistance to radiation and drug-based therapies.

【 授权许可】

CC BY   
© Mezencev et al. 2016