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Cancer Chemotherapy and Pharmacology

Published in:

01-08-2018 | Original Article

Overexpression of ABCB4 contributes to acquired doxorubicin resistance in breast cancer cells in vitro

Authors: Jia-Feng Huang, Chun-Jie Wen, Guo-Zhi Zhao, Yi Dai, Ying Li, Lan-Xiang Wu, Hong-Hao Zhou

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2018

Abstract

Purpose

Doxorubicin is one of the most active agents in the first-line therapy for metastatic breast cancer, but its utility is partially limited by the frequent emergence of doxorubicin resistance. In this study, we aimed to investigate the role of ATP-binding cassette sub-family B, member 4 (ABCB4) in acquired doxorubicin resistance in breast cancer cells, as well as its potential mechanism.

Methods

In doxorubicin-sensitive and -resistant breast cancer cell lines MCF-7 and MDA-MB-231, the expression levels of ABCB4 were detected using real-time quantitative PCR and Western blot analysis, the DNA methylation and histone acetylation status of ABCB4 gene were investigated by bisulfite-sequencing PCR (BSP) and chromatin immunoprecipitation (ChIP) assays, and the doxorubicin sensitivity and intracellular doxorubicin accumulation were observed using cell cytotoxicity assay and flow cytometry. In Madin–Darby Canine Kidney (MDCKII) cells, In vitro transport assay was used to assess the ABCB4-mediated transport of doxorubicin.

Results

ABCB4 was overexpressed in doxorubicin-resistant breast cancer cells compared to their doxorubicin-sensitive counterparts, which was associated with reduced DNA methylation as well as increased histone acetylation at the ABCB4 promoter. ABCB4 could actively pump doxorubicin out of the cells, and knockdown of ABCB4 increased doxorubicin sensitivity and intracellular accumulation in doxorubicin-resistant breast cancer cells.

Conclusions

Our results indicate that ABCB4 is overexpressed in breast cancer cells with acquired doxorubicin resistance, which could be attributed, at least partially, to the epigenetic modifications of ABCB4 gene. ABCB4 mediates the efflux transport of doxorubicin, and contributes to the acquired resistance of doxorubicin in breast cancer cells.

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Title: Overexpression of ABCB4 contributes to acquired doxorubicin resistance in breast cancer cells in vitro
Authors: Jia-Feng Huang
Chun-Jie Wen
Guo-Zhi Zhao
Yi Dai
Ying Li
Lan-Xiang Wu
Hong-Hao Zhou
Publication date: 01-08-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-018-3603-y

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Abstract

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