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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

verfasst von: 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

Erschienen in: Tumor Biology | Ausgabe 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, MCF7_RES and MDA_RES, 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. MCF7_RES and MDA_RES 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 MCF7_RES and MDA_RES. 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 MCF7_RES and cancer testis antigen family in MDA_RES. Also, upregulated expression of various ABC transporters, ECM-associated proteins, and lysosomal proteins was identified in both resistant cell lines. Finally, MCF7_RES and MDA_RES presented with cross-resistance to epirubicin, but only MDA_RES 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 MCF7_RES and MDA_RES were cross-resistant to epirubicin (Pgp substrate), but only MDA_RES was cross-resistant to oxaliplatin (non-Pgp substrate).

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Titel: 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
verfasst von: 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
Publikationsdatum: 01.06.2015
Verlag: Springer Netherlands
Erschienen in: Tumor Biology / Ausgabe 6/2015
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-015-3072-4

Springer Medizin

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

Abstract

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Springer Medizin

Abstract

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