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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines

Authors: Haatisha Jandu, Kristina Aluzaite, Louise Fogh, Sebastian Wingaard Thrane, Julie B. Noer, Joanna Proszek, Khoa Nguyen Do, Stine Ninel Hansen, Britt Damsgaard, Signe Lykke Nielsen, Magnus Stougaard, Birgitta R. Knudsen, José Moreira, Petra Hamerlik, Madhavsai Gajjar, Marcel Smid, John Martens, John Foekens, Yves Pommier, Nils Brünner, Anne-Sofie Schrohl, Jan Stenvang

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30 % response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in BC.

Methods

We established BC cell lines with acquired or de novo resistance to SN-38, by exposing the human BC cell lines MCF-7 and MDA-MB-231 to either stepwise increasing concentrations over 6 months or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer resistance protein (ABCG2/BCRP) drug efflux pump.

Results

We found that the resistant cell lines showed 7–100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance.

Conclusions

Based on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan.
Appendix
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Metadata
Title
Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines
Authors
Haatisha Jandu
Kristina Aluzaite
Louise Fogh
Sebastian Wingaard Thrane
Julie B. Noer
Joanna Proszek
Khoa Nguyen Do
Stine Ninel Hansen
Britt Damsgaard
Signe Lykke Nielsen
Magnus Stougaard
Birgitta R. Knudsen
José Moreira
Petra Hamerlik
Madhavsai Gajjar
Marcel Smid
John Martens
John Foekens
Yves Pommier
Nils Brünner
Anne-Sofie Schrohl
Jan Stenvang
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2071-1

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