Abstract LB-246: Epithelial-mesenchymal transition (EMT) does not necessarily decrease the sensitivity of cancer cells to chemotherapeutic agents

Abstract

Abstract Epithelial to mesenchymal transition (EMT) has been recently associated with metastatic competence and therapy resistance of cancer cells and the need for development of EMT-targeted therapies has been emphasized. In this report we address the differential responses of breast cancer cell lines with epithelial and mesenchymal phenotypes to anticancer agents using pharmacoinformatics and experimental approaches. First, we identified breast cancer cell lines with epithelial-like and mesenchymal-like phenotypes among the National Cancer Institute (NCI) panel of 60 cell lines and analyzed their differential responses to 10,081 anticancer agents. Second, we evaluated chemotherapeutic response of a mesenchymal-like isogenic breast cancer cell line (MCF-7-Snail) stably transfected to express the EMT-inducing Snail transcription factor and its epithelial-like precursor cell line transfected with the control plasmid (MCF-7-neo). The results of both approaches are inconsistent with the claim that mesenchymal-like cancer cells are generally more resistant to anticancer agents. We found that most of the 10,081 agents examined did not display significantly different potencies between epithelial-like and mesenchymal-like cells. Of the 10,081 anti-cancer agents examined, only 78 displayed consistent differences in effect between epithelial-like and mesenchymal-like cells and all of these agents displayed a more potent effect against mesenchymal-like cell lines. MCF-7-Snail cells were found to be more sensitive to the cytotoxic effects of doxorubicin, 5-FU and methotrexate, while MCF-7-neo cells were more sensitive to gemcitabine and docetaxel and both of these isogenic cell lines were equally responsive to mitomycin C and vincristine. The relatively lower sensitivity of MCF-Snail cells to docetaxel and gemcitabine can be explained by their overexpression of TUBB4 and RRM1, respectively, as demonstrated by gene expression analysis (U133 Plus 2.0 Affymetrix microarrays). In contrast, the higher sensitivity of MCF-7-Snail cells to 5-FU may be due to the down-regulation of the DPYD gene in these cells. Compared to isogenic epithelial cells, MCF-7-Snail cells display down-regulation of the anti-apoptotic genes XIAP, BCL2L1 and NAIP. Collectively, our results indicate that EMT per se does not generally result in a greater resistance of cancer cells to chemotherapeutic agents, but it may, in some instances, result in increased sensitivity of cancer cells to specific chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-246. doi:1538-7445.AM2012-LB-246