Abstract
BackgroundClinical resistance to chemotherapeutic agents is one of the major hindrances in the treatment of human cancers. Erythroblastosis virus E26 oncogene homolog 1 (ETS1) is involved in the drug resistance of various cancer cells, and is overexpressed in drug-resistant human breast cancer cell lines. In this study, we investigated the effects of ETS1 on adriamycin resistance in MCF-7/ADR cells.MethodssiRNAs against ETS1 or negative control siRNAs was transfected to MCF-7/ADR breast cancer cells. Reverse transcription-PCR and Western blotting were used to determine the mRNA and protein expression of ETS1 and MDR1. The cytotoxicity of adriamycin was assessed using the MTT assay. Drug efflux was investigated by flow cytometry using the Rhodamine 123 intracellular accumulation assay.ResultsETS1 mRNA and protein was significantly overexpressed in MCF-7/ADR cells, compared to MCF-7 cells. ETS1 siRNA successfully silenced ETS1 mRNA and protein expression. Silencing of ETS1 also significantly reduced the mRNA and protein expression levels of MDR1 (multidrug resistance 1; also known as ABCB1, P-glycoprotein/P-gp), which is a major ATP-binding cassette (ABC) transporter linked to multi-drug resistance in cancer cells. Silencing of ETS1 significantly increased the sensitivity of MCF-7/ADR cells to adriamycin, compared to cells transfected with negative control siRNA. In addition, intracellular accumulation of Rhodamine 123 significantly increased in MCF-7/ADR cells transfected with ETS1 siRNA, indicating that silencing of ETS1 may reduce drug efflux.ConclusionsThis study demonstrates that drug resistance can be effectively reversed in adriamycin-resistant breast carcinoma cells through delivery of siRNAs targeting ETS1.
Highlights
Breast cancer is a systemic disease, with the primary tumor representing the localized form of the disease
In this study we investigated the effects of ETS1 on adriamycin resistance in MCF-7/ADR cells, which are typical multidrug-resistant human breast cancer cells that were selected by exposure to adriamycin [13]
ETS1 is up-regulated in MCF-7/ADR cells compared to MCF-7 cells Initially, we determined the mRNA and protein expression of multidrug resistance 1 (MDR1) in the MCF-7 and MCF-7/ADR cells to confirm the Adriamycin-resistance
Summary
Breast cancer is a systemic disease, with the primary tumor representing the localized form of the disease. The resistance of tumor cells to multiple chemotherapeutic agents is a major obstacle to the success of cancer chemotherapy, and has been strongly associated with treatment failure [1]. Multidrug resistance (MDR) refers to the resistance of tumors to a single cytotoxic drug, but crossresistance to a wide range of drugs with unrelated function and structure [2]. Clinical resistance to chemotherapeutic agents is one of the major hindrances in the treatment of human cancers. Erythroblastosis virus E26 oncogene homolog 1 (ETS1) is involved in the drug resistance of various cancer cells, and is overexpressed in drug-resistant human breast cancer cell lines. We investigated the effects of ETS1 on adriamycin resistance in MCF-7/ADR cells
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