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

BMC Cancer

Research Article

Petra Hamerlik¹  Madhavsai Gajjar¹  Khoa Nguyen Do²  Birgitta R. Knudsen³  Joanna Proszek⁴  Magnus Stougaard⁴  John Martens⁵  John Foekens⁵  Marcel Smid⁵  Sebastian Wingaard Thrane⁶  Jan Stenvang⁶  Kristina Aluzaite⁶  Julie B. Noer⁶  Louise Fogh⁶  Anne-Sofie Schrohl⁶  Haatisha Jandu⁶  Nils Brünner⁶  Stine Ninel Hansen⁶  Signe Lykke Nielsen⁶  Britt Damsgaard⁶  José Moreira⁶  Yves Pommier⁷ 

[1] Brain Tumor Biology, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100, Copenhagen, Denmark;DTU Multiassay Core (DMAC), Technical University of Denmark, Kemitorvet Building 208, DK-2800, Lyngby, Denmark;Department of Molecular Biology and Genetics, Aarhus University, C.F. Møllers Allé 3, 8000, Aarhus C, Denmark;Department of Pathology, Aarhus University Hospital, Noerrebrogade 44, building 18B, 8000, Aarhus C, Denmark;Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC, Rotterdam, The Netherlands;Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Section for Molecular Disease Biology and Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Strandboulevarden 49, DK-2100, Copenhagen, Denmark;National Institutes of Health, National Cancer Institute, Center for Cancer Research, Developmental Therapeutics Branch and Laboratory of Molecular, Pharmacology, 37 Convent Drive, Building 37, Room 5068, 20892-4255, Bethesda, MD, USA;

关键词: Breast cancer;    Topoisomerase I;    Irinotecan;    SN-38;    Resistance;    ABCG2/BCRP;   

DOI  :  10.1186/s12885-016-2071-1

 received in 2015-07-21, accepted in 2016-01-18,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundStudies 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.MethodsWe 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.ResultsWe 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.ConclusionsBased 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.

【 授权许可】

CC BY   
© Jandu et al. 2016