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Tumor Biology
Published in: Tumor Biology 6/2015

01-06-2015 | Research Article

Acquisition of docetaxel resistance in breast cancer cells reveals upregulation of ABCB1 expression as a key mediator of resistance accompanied by discrete upregulation of other specific genes and pathways

Authors: Stine Ninel Hansen, David Westergaard, Mathilde Borg Houlberg Thomsen, Mette Vistesen, Khoa Nguyen Do, Louise Fogh, Kirstine C. Belling, Jun Wang, Huanming Yang, Ramneek Gupta, Henrik J. Ditzel, José Moreira, Nils Brünner, Jan Stenvang, Anne-Sofie Schrohl

Published in: Tumor Biology | Issue 6/2015

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Abstract

The microtubule-targeting taxanes are important in breast cancer therapy, but no predictive biomarkers have yet been identified with sufficient scientific evidence to allow clinical routine use. The purposes of the present study were to develop a cell-culture-based discovery platform for docetaxel resistance and thereby identify key molecular mechanisms and predictive molecular characteristics to docetaxel resistance. Two docetaxel-resistant cell lines, MCF7RES and MDARES, were generated from their respective parental cell lines MCF-7 and MDA-MB-231 by stepwise selection in docetaxel dose increments over 15 months. The cell lines were characterized regarding sensitivity to docetaxel and other chemotherapeutics and subjected to transcriptome-wide mRNA microarray profiling. MCF7RES and MDARES exhibited a biphasic growth inhibition pattern at increasing docetaxel concentrations. Gene expression analysis singled out ABCB1, which encodes permeability glycoprotein (Pgp), as the top upregulated gene in both MCF7RES and MDARES. Functional validation revealed Pgp as a key resistance mediator at low docetaxel concentrations (first-phase response), whereas additional resistance mechanisms appeared to be prominent at higher docetaxel concentrations (second-phase response). Additional resistance mechanisms were indicated by gene expression profiling, including genes in the interferon-inducible protein family in MCF7RES and cancer testis antigen family in MDARES. Also, upregulated expression of various ABC transporters, ECM-associated proteins, and lysosomal proteins was identified in both resistant cell lines. Finally, MCF7RES and MDARES presented with cross-resistance to epirubicin, but only MDARES showed cross-resistance to oxaliplatin. In conclusion, Pgp was identified as a key mediator of resistance to low docetaxel concentrations with other resistance mechanisms prominent at higher docetaxel concentrations. Supporting Pgp upregulation as one major mechanism of taxane resistance and cell-line-specific alterations as another, both MCF7RES and MDARES were cross-resistant to epirubicin (Pgp substrate), but only MDARES was cross-resistant to oxaliplatin (non-Pgp substrate).
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Metadata
Title
Acquisition of docetaxel resistance in breast cancer cells reveals upregulation of ABCB1 expression as a key mediator of resistance accompanied by discrete upregulation of other specific genes and pathways
Authors
Stine Ninel Hansen
David Westergaard
Mathilde Borg Houlberg Thomsen
Mette Vistesen
Khoa Nguyen Do
Louise Fogh
Kirstine C. Belling
Jun Wang
Huanming Yang
Ramneek Gupta
Henrik J. Ditzel
José Moreira
Nils Brünner
Jan Stenvang
Anne-Sofie Schrohl
Publication date
01-06-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 6/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3072-4

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