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

Research output: Contribution to journalJournal articleResearchpeer-review

Haatisha Jandu, Kristina Aluzaité, Louise Fogh, Sebastian Wingaard Thrane, Julie B Noer, Joanna Proszek, Khoa Nguyen Do, Stine Ninel Hansen, Britt Damsgaard-Hansen, Signe Lykke Nielsen, Magnus Stougaard, Birgitta R. Knudsen, José Moreira, Petra Hamerlik, Madhavsai Gajjar, Marcel Smid, John Martens, John Foekens, Yves Pommier, Nils Brünner & 2 others Anne-Sofie Schrohl Rasmussen, Jan Stenvang

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.

Original languageEnglish
Article number34
JournalB M C Cancer
Volume16
Number of pages13
ISSN1471-2407
DOIs
Publication statusPublished - 22 Jan 2016

ID: 160449210