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BMC Cancer ; 16: 34, 2016 Jan 22.
Article in English | MEDLINE | ID: mdl-26801902

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.


Subject(s)
ATP-Binding Cassette Transporters/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Camptothecin/analogs & derivatives , DNA Topoisomerases, Type I/genetics , Neoplasm Proteins/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/biosynthesis , Antigens, Neoplasm/genetics , Breast Neoplasms/pathology , Camptothecin/administration & dosage , Camptothecin/adverse effects , DNA Topoisomerases, Type I/biosynthesis , DNA Topoisomerases, Type II/genetics , DNA-Binding Proteins/genetics , Docetaxel , Drug Resistance, Neoplasm/genetics , Female , Gene Dosage/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Irinotecan , MCF-7 Cells , Neoplasm Proteins/biosynthesis , Poly-ADP-Ribose Binding Proteins , Taxoids/administration & dosage
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