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

BMC Cancer
Haatisha JanduJan Stenvang

Abstract

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. 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. 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 an...Continue Reading

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Sep 8, 2017·International Journal of Molecular Sciences·Dorte Lisbet NielsenBirgitte Martine Viuff
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Dec 7, 2019·ACS Central Science·Krysten A JonesBryan C Dickinson

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Datasets Mentioned

BETA
GSE41313

Methods Mentioned

BETA
MDA
Tandem Repeat
PCR
fluorescence-activated cell sorting
chips
electrophoresis
MDAacq
biopsies

Clinical Trials Mentioned

NCT01245192
NCT01051635
NCT01794104

Software Mentioned

ProteinSimple
GraphPad Prism
R
Nexus
MetaCore
BEACON
FlowJo
Clusterprofiler
Excel

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