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Topoisomerase I activity and sensitivity to camptothecin in breast cancer-derived cells: a comparative study

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Topoisomerase I activity and sensitivity to camptothecin in breast cancer-derived cells : a comparative study. / Tesauro, Cinzia; Simonsen, Anne Katrine; Andersen, Marie Bech; Petersen, Kamilla Wandsoe; Kristoffersen, Emil Laust; Algreen, Line; Hansen, Noriko Yokoyama; Andersen, Anne Bech; Jakobsen, Ann Katrine; Stougaard, Magnus; Gromov, Pavel; Knudsen, Birgitta R; Gromova, Irina.

In: BMC Cancer, Vol. 19, No. 1, 1158, 29.11.2019.

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@article{353fadf6b2c14975a02bbda641464b27,
title = "Topoisomerase I activity and sensitivity to camptothecin in breast cancer-derived cells: a comparative study",
abstract = "BACKGROUND: Camptothecin (CPT) and its derivatives are currently used as second- or third-line treatment for patients with endocrine-resistant breast cancer (BC). These drugs convert nuclear enzyme DNA topoisomerase I (TOP1) to a cell poison with the potential to damage DNA by increasing the half-life of TOP1-DNA cleavage complexes (TOP1cc), ultimately resulting in cell death. In small and non-randomized trials for BC, researchers have observed extensive variation in CPT response rates, ranging from 14 to 64%. This variability may be due to the absence of reliable selective parameters for patient stratification. BC cell lines may serve as feasible models for generation of functional criteria that may be used to predict drug sensitivity for patient stratification and, thus, lead to more appropriate applications of CPT in clinical trials. However, no study published to date has included a comparison of multiple relevant parameters and CPT response across cell lines corresponding to specific BC subtypes.METHOD: We evaluated the levels and possible associations of seven parameters including the status of the TOP1 gene (i.e. amplification), TOP1 protein expression level, TOP1 activity and CPT susceptibility, activity of the tyrosyl-DNA phosphodiesterase 1 (TDP1), the cellular CPT response and the cellular growth rate across a representative panel of BC cell lines, which exemplifies three major BC subtypes: Luminal, HER2 and TNBC.RESULTS: In all BC cell lines analyzed (without regard to subtype classification), we observed a significant overall correlation between growth rate and CPT response. In cell lines derived from Luminal and HER2 subtypes, we observed a correlation between TOP1 gene copy number, TOP1 activity, and CPT response, although the data were too limited for statistical analyses. In cell lines representing Luminal and TNBC subtypes, we observed a direct correlation between TOP1 protein abundancy and levels of enzymatic activity. In all three subtypes (Luminal, HER2, and TNBC), TOP1 exhibits approximately the same susceptibility to CPT. Of the three subtypes examined, the TNBC-like cell lines exhibited the highest CPT sensitivity and were characterized by the fastest growth rate. This indicates that breast tumors belonging to the TNBC subtype, may benefit from treatment with CPT derivatives.CONCLUSION: TOP1 activity is not a marker for CPT sensitivity in breast cancer.",
author = "Cinzia Tesauro and Simonsen, {Anne Katrine} and Andersen, {Marie Bech} and Petersen, {Kamilla Wandsoe} and Kristoffersen, {Emil Laust} and Line Algreen and Hansen, {Noriko Yokoyama} and Andersen, {Anne Bech} and Jakobsen, {Ann Katrine} and Magnus Stougaard and Pavel Gromov and Knudsen, {Birgitta R} and Irina Gromova",
year = "2019",
month = nov,
day = "29",
doi = "10.1186/s12885-019-6371-0",
language = "English",
volume = "19",
journal = "B M C Cancer",
issn = "1471-2407",
publisher = "BioMed Central Ltd.",
number = "1",

}

RIS

TY - JOUR

T1 - Topoisomerase I activity and sensitivity to camptothecin in breast cancer-derived cells

T2 - a comparative study

AU - Tesauro, Cinzia

AU - Simonsen, Anne Katrine

AU - Andersen, Marie Bech

AU - Petersen, Kamilla Wandsoe

AU - Kristoffersen, Emil Laust

AU - Algreen, Line

AU - Hansen, Noriko Yokoyama

AU - Andersen, Anne Bech

AU - Jakobsen, Ann Katrine

AU - Stougaard, Magnus

AU - Gromov, Pavel

AU - Knudsen, Birgitta R

AU - Gromova, Irina

PY - 2019/11/29

Y1 - 2019/11/29

N2 - BACKGROUND: Camptothecin (CPT) and its derivatives are currently used as second- or third-line treatment for patients with endocrine-resistant breast cancer (BC). These drugs convert nuclear enzyme DNA topoisomerase I (TOP1) to a cell poison with the potential to damage DNA by increasing the half-life of TOP1-DNA cleavage complexes (TOP1cc), ultimately resulting in cell death. In small and non-randomized trials for BC, researchers have observed extensive variation in CPT response rates, ranging from 14 to 64%. This variability may be due to the absence of reliable selective parameters for patient stratification. BC cell lines may serve as feasible models for generation of functional criteria that may be used to predict drug sensitivity for patient stratification and, thus, lead to more appropriate applications of CPT in clinical trials. However, no study published to date has included a comparison of multiple relevant parameters and CPT response across cell lines corresponding to specific BC subtypes.METHOD: We evaluated the levels and possible associations of seven parameters including the status of the TOP1 gene (i.e. amplification), TOP1 protein expression level, TOP1 activity and CPT susceptibility, activity of the tyrosyl-DNA phosphodiesterase 1 (TDP1), the cellular CPT response and the cellular growth rate across a representative panel of BC cell lines, which exemplifies three major BC subtypes: Luminal, HER2 and TNBC.RESULTS: In all BC cell lines analyzed (without regard to subtype classification), we observed a significant overall correlation between growth rate and CPT response. In cell lines derived from Luminal and HER2 subtypes, we observed a correlation between TOP1 gene copy number, TOP1 activity, and CPT response, although the data were too limited for statistical analyses. In cell lines representing Luminal and TNBC subtypes, we observed a direct correlation between TOP1 protein abundancy and levels of enzymatic activity. In all three subtypes (Luminal, HER2, and TNBC), TOP1 exhibits approximately the same susceptibility to CPT. Of the three subtypes examined, the TNBC-like cell lines exhibited the highest CPT sensitivity and were characterized by the fastest growth rate. This indicates that breast tumors belonging to the TNBC subtype, may benefit from treatment with CPT derivatives.CONCLUSION: TOP1 activity is not a marker for CPT sensitivity in breast cancer.

AB - BACKGROUND: Camptothecin (CPT) and its derivatives are currently used as second- or third-line treatment for patients with endocrine-resistant breast cancer (BC). These drugs convert nuclear enzyme DNA topoisomerase I (TOP1) to a cell poison with the potential to damage DNA by increasing the half-life of TOP1-DNA cleavage complexes (TOP1cc), ultimately resulting in cell death. In small and non-randomized trials for BC, researchers have observed extensive variation in CPT response rates, ranging from 14 to 64%. This variability may be due to the absence of reliable selective parameters for patient stratification. BC cell lines may serve as feasible models for generation of functional criteria that may be used to predict drug sensitivity for patient stratification and, thus, lead to more appropriate applications of CPT in clinical trials. However, no study published to date has included a comparison of multiple relevant parameters and CPT response across cell lines corresponding to specific BC subtypes.METHOD: We evaluated the levels and possible associations of seven parameters including the status of the TOP1 gene (i.e. amplification), TOP1 protein expression level, TOP1 activity and CPT susceptibility, activity of the tyrosyl-DNA phosphodiesterase 1 (TDP1), the cellular CPT response and the cellular growth rate across a representative panel of BC cell lines, which exemplifies three major BC subtypes: Luminal, HER2 and TNBC.RESULTS: In all BC cell lines analyzed (without regard to subtype classification), we observed a significant overall correlation between growth rate and CPT response. In cell lines derived from Luminal and HER2 subtypes, we observed a correlation between TOP1 gene copy number, TOP1 activity, and CPT response, although the data were too limited for statistical analyses. In cell lines representing Luminal and TNBC subtypes, we observed a direct correlation between TOP1 protein abundancy and levels of enzymatic activity. In all three subtypes (Luminal, HER2, and TNBC), TOP1 exhibits approximately the same susceptibility to CPT. Of the three subtypes examined, the TNBC-like cell lines exhibited the highest CPT sensitivity and were characterized by the fastest growth rate. This indicates that breast tumors belonging to the TNBC subtype, may benefit from treatment with CPT derivatives.CONCLUSION: TOP1 activity is not a marker for CPT sensitivity in breast cancer.

U2 - 10.1186/s12885-019-6371-0

DO - 10.1186/s12885-019-6371-0

M3 - Journal article

C2 - 31783818

VL - 19

JO - B M C Cancer

JF - B M C Cancer

SN - 1471-2407

IS - 1

M1 - 1158

ER -