Multiple mechanisms underlying acquired resistance to taxanes in selected docetaxel-resistant MCF-7 breast cancer cells

BMC Cancer

Harris Wang²  The Vo²  Ali Hajar²  Sarah Li²  Xinmei Chen²  Amadeo M Parissenti¹  David N Brindley³  Zhixiang Wang² 

[1] Regional Cancer Program, Sudbury Regional Hospital, Sudbury, ON, Canada

[2] Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada

[3] Department of Biochemistry and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada

关键词: Microtubule dynamics;    β-tubulin isoforms;    ABC proteins;    MCF-7 cell;    Chemoresistance;    Doxorubicin;    Taxane;    Breast cancer;   

Others  :  859119
DOI  :  10.1186/1471-2407-14-37

 received in 2013-12-10, accepted in 2014-01-17,  发布年份 2014

【 摘 要 】

Background

Chemoresistance is a major factor involved in a poor response and reduced overall survival in patients with advanced breast cancer. Although extensive studies have been carried out to understand the mechanisms of chemoresistance, many questions remain unanswered.

Methods

In this research, we used two isogenic MCF-7 breast cancer cell lines selected for resistance to doxorubicin (MCF-7_DOX) or docetaxel (MCF-7_TXT) and the wild type parental cell line (MCF-7_CC) to study mechanisms underlying acquired resistance to taxanes in MCF-7_TXT cells. Cytotoxicity assay, immunoblotting, indirect immunofluorescence and live imaging were used to study the drug resistance, the expression levels of drug transporters and various tubulin isoforms, apoptosis, microtubule formation, and microtubule dynamics.

Results

MCF-7_TXT cells were cross resistant to paclitaxel, but not to doxorubicin. MCF-7_DOX cells were not cross-resistant to taxanes. We also showed that multiple mechanisms are involved in the resistance to taxanes in MCF-7_TXT cells. Firstly, MCF-7_TXT cells express higher level of ABCB1. Secondly, the microtubule dynamics of MCF-7_TXT cells are weak and insensitive to the docetaxel treatment, which may partially explain why docetaxel is less effective in inducing M-phase arrest and apoptosis in MCF-7_TXT cells in comparison with MCF-7_CC cells. Moreover, MCF-7_TXT cells express relatively higher levels of β2- and β4-tubulin and relatively lower levels of β3-tubulin than both MCF-7_CC and MCF-7_DOX cells. The subcellular localization of various β-tubulin isoforms in MCF-7_TXT cells is also different from that in MCF-7_CC and MCF-7_DOX cells.

Conclusion

Multiple mechanisms are involved in the resistance to taxanes in MCF-7_TXT cells. The high expression level of ABCB1, the specific composition and localization of β-tubulin isoforms, the weak microtubule dynamics and its insensitivity to docetaxel may all contribute to the acquired resistance of MCF-7_TXT cells to taxanes.

【 授权许可】

   
2014 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

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