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

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  • Haatisha Jandu, 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
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  • Kristina Aluzaite, 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
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  • Louise Fogh, 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, Danmark
  • Sebastian Wingaard Thrane, 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, Danmark
  • Julie B Noer, 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, Danmark
  • Joanna Proszek, Department of Pathology, Aarhus University Hospital, Aarhus
  • ,
  • Khoa Nguyen Do, Multiassay Core (DMAC), Technical University of Denmark, Danmark
  • Stine Ninel Hansen, 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, Danmark
  • Britt Damsgaard, 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, Danmark
  • Signe Lykke Nielsen, 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
  • ,
  • Magnus Stougaard
  • Birgitta R Knudsen
  • José Moreira, 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
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  • Petra Hamerlik, Brain Tumor Biology, Danish Cancer Society Research Center
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  • Madhavsai Gajjar, Brain Tumor Biology, Danish Cancer Society Research Center, Danmark
  • Marcel Smid, Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands
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  • John Martens, Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands
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  • John Foekens, Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands
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  • Yves Pommier, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda
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  • Nils Brünner, 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
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  • Anne-Sofie Schrohl, 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
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  • Jan Stenvang, 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

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.

OriginalsprogEngelsk
Artikelnummer34
TidsskriftBMC Cancer
Vol/bind16
Nummer1
Antal sider13
ISSN1471-2407
DOI
StatusUdgivet - 22 jan. 2016

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