Abstract
BackgroundChemoresistance 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.MethodsIn this research, we used two isogenic MCF-7 breast cancer cell lines selected for resistance to doxorubicin (MCF-7DOX) or docetaxel (MCF-7TXT) and the wild type parental cell line (MCF-7CC) to study mechanisms underlying acquired resistance to taxanes in MCF-7TXT 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.ResultsMCF-7TXT cells were cross resistant to paclitaxel, but not to doxorubicin. MCF-7DOX cells were not cross-resistant to taxanes. We also showed that multiple mechanisms are involved in the resistance to taxanes in MCF-7TXT cells. Firstly, MCF-7TXT cells express higher level of ABCB1. Secondly, the microtubule dynamics of MCF-7TXT 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-7TXT cells in comparison with MCF-7CC cells. Moreover, MCF-7TXT cells express relatively higher levels of β2- and β4-tubulin and relatively lower levels of β3-tubulin than both MCF-7CC and MCF-7DOX cells. The subcellular localization of various β-tubulin isoforms in MCF-7TXT cells is also different from that in MCF-7CC and MCF-7DOX cells.ConclusionMultiple mechanisms are involved in the resistance to taxanes in MCF-7TXT 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-7TXT cells to taxanes.
Highlights
Chemoresistance is a major factor involved in a poor response and reduced overall survival in patients with advanced breast cancer
We showed that multiple mechanisms are involved in the resistance to taxanes in MCF-7TXT cells
The three cell lines used in the experiments include Docetaxel-resistant MCF-7 cells selected with increased docetaxel concentration (MCF-7TXT), Doxorubicin-resistant MCF-7 cells selected with increased doxorubicin concentration (MCF-7DOX), and the parent non-resistant MCF-7 cell line (MCF-7CC) [25]
Summary
Chemoresistance is a major factor involved in a poor response and reduced overall survival in patients with advanced breast cancer. The incidence of breast cancer is continuously increasing, with more than one million reported new cases diagnosed per year worldwide [1,2,3] Among these cases, 20-30% present with metastatic or locally advanced disease, Chemotherapy is often used to treat breast cancer in both the adjuvant and neoadjuvant settings and often involves the administration of anthracyclines together with (or followed by) taxanes. While the mechanisms of action are not yet completely understood, one very important component of the activity of doxorubicin is its interaction with chromatin and its constitutive components: DNA and histones. These interactions lead to chromatin unfolding and aggregation. Topoisomerase II mediated DNA damage by doxorubicin is followed by G1 and G2 growth arrest and induction of apoptosis, which correlates with tumor response and patient outcomes [1,10,11,12]
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