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

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.

Efficacy and Safety Assessment of Paclitaxel in Patients with Docetaxel-Resistant Esophageal Squamous Cell Carcinoma

“…Among these, Hanauske et al [21] reported incomplete cross-resistance between PTX and DTX in breast, lung, ovary, colon and prostate cancer cell lines, and showed sensitivity to PTX after DTX treatment in 10 cell lines. However, complete cross-resistance between PTX and DTX was observed in MCF-7 cells [22], indicating varying degrees of cross-resistance between cancer types. Several clinical analyses also show incomplete cross-resistance between PTX and DTX in breast [23,24], ovarian [25] and gastric cancer [15] patients.…”

Differentially expressed proteins in human MCF-7 breast cancer cells sensitive and resistant to paclitaxel

“…Nevertheless, the exact mechanism of cell death induced by this mitotic arrest has not been revealed yet. Apoptosis represents one possible mechanism [5,6], other experiments described induction of mitotic catastrophe as another one [7]. A hypothesis exists that switching between these two mechanisms could be ruled by different concentrations of taxanes [8].…”

Roles of the Bcl-2/Bax Ratio, Caspase-8 and 9 in Resistance of Breast Cancer Cells to Paclitaxel

“…Investigation of molecular mechanisms involved in the chemoresistance can be helpful in designing novel strategies in cancer treatment. Paclitaxel resistant MCF-7 cell line was developed by some of researchers for study about resistance mechanisms and involved molecules in this cell line for example; paclitaxel binding proteins, extracellular matrix proteins, drug transporters and β-tubulin isoforms (Hembruff et al, 2008;Iseri et al, 2010;Zuo et al, 2010;Wang et al, 2014). In this study, we investigated role of some of key apoptotic proteins in paclitaxel resistant breast cancer cells.…”