Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines. / Jandu, Haatisha; Aluzaité, Kristina; Fogh, Louise; Thrane, Sebastian Wingaard; Noer, Julie B; Proszek, Joanna; Nguyen Do, Khoa; Hansen, Stine Ninel; Damsgaard-Hansen, Britt; Nielsen, Signe Lykke; Stougaard, Magnus; Knudsen, Birgitta R.; Moreira, José; Hamerlik, Petra; Gajjar, Madhavsai; Smid, Marcel; Martens, John; Foekens, John; Pommier, Yves; Brünner, Nils; Rasmussen, Anne-Sofie Schrohl; Stenvang, Jan.
In: B M C Cancer, Vol. 16, 34, 22.01.2016.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines
AU - Jandu, Haatisha
AU - Aluzaité, Kristina
AU - Fogh, Louise
AU - Thrane, Sebastian Wingaard
AU - Noer, Julie B
AU - Proszek, Joanna
AU - Nguyen Do, Khoa
AU - Hansen, Stine Ninel
AU - Damsgaard-Hansen, Britt
AU - Nielsen, Signe Lykke
AU - Stougaard, Magnus
AU - Knudsen, Birgitta R.
AU - Moreira, José
AU - Hamerlik, Petra
AU - Gajjar, Madhavsai
AU - Smid, Marcel
AU - Martens, John
AU - Foekens, John
AU - Pommier, Yves
AU - Brünner, Nils
AU - Rasmussen, Anne-Sofie Schrohl
AU - Stenvang, Jan
PY - 2016/1/22
Y1 - 2016/1/22
N2 - 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.
AB - 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.
KW - Faculty of Social Sciences
KW - Breast cancer
KW - Topoisomerase I
KW - Irinotecan
KW - SN-38
KW - Resistance
KW - ABCG2/BCRP
U2 - 10.1186/s12885-016-2071-1
DO - 10.1186/s12885-016-2071-1
M3 - Journal article
C2 - 26801902
VL - 16
JO - B M C Cancer
JF - B M C Cancer
SN - 1471-2407
M1 - 34
ER -
ID: 160449210