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Protein Expression of DNA Damage Repair Proteins Dictates Response to Topoisomerase and PARP Inhibitors in Triple-Negative Breast Cancer

Patients with metastatic triple-negative breast cancer (TNBC) have a poor prognosis. New approaches for the treatment of TNBC are needed to improve patient survival. The concept of synthetic lethality, brought about by inactivating complementary DNA repair pathways, has been proposed as a promising...

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Autores principales: Boerner, Julie L., Nechiporchik, Nicole, Mueller, Kelly L., Polin, Lisa, Heilbrun, Lance, Boerner, Scott A., Zoratti, Gina L., Stark, Karri, LoRusso, Patricia M., Burger, Angelika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361640/
https://www.ncbi.nlm.nih.gov/pubmed/25774912
http://dx.doi.org/10.1371/journal.pone.0119614
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author Boerner, Julie L.
Nechiporchik, Nicole
Mueller, Kelly L.
Polin, Lisa
Heilbrun, Lance
Boerner, Scott A.
Zoratti, Gina L.
Stark, Karri
LoRusso, Patricia M.
Burger, Angelika
author_facet Boerner, Julie L.
Nechiporchik, Nicole
Mueller, Kelly L.
Polin, Lisa
Heilbrun, Lance
Boerner, Scott A.
Zoratti, Gina L.
Stark, Karri
LoRusso, Patricia M.
Burger, Angelika
author_sort Boerner, Julie L.
collection PubMed
description Patients with metastatic triple-negative breast cancer (TNBC) have a poor prognosis. New approaches for the treatment of TNBC are needed to improve patient survival. The concept of synthetic lethality, brought about by inactivating complementary DNA repair pathways, has been proposed as a promising therapeutic option for these tumors. The TNBC tumor type has been associated with BRCA mutations, and inhibitors of Poly (ADP-ribose) polymerase (PARP), a family of proteins that facilitates DNA repair, have been shown to effectively kill BRCA defective tumors by preventing cells from repairing DNA damage, leading to a loss of cell viability and clonogenic survival. Here we present preclinical efficacy results of combining the PARP inhibitor, ABT-888, with CPT-11, a topoisomerase I inhibitor. CPT-11 binds to topoisomerase I at the replication fork, creating a bulky adduct that is recognized as damaged DNA. When DNA damage was stimulated with CPT-11, protein expression of the nucleotide excision repair enzyme ERCC1 inversely correlated with cell viability, but not clonogenic survival. However, 4 out of the 6 TNBC cells were synergistically responsive by cell viability and 5 out of the 6 TNBC cells were synergistically responsive by clonogenic survival to the combination of ABT-888 and CPT-11. In vivo, the BRCA mutant cell line MX-1 treated with CPT-11 alone demonstrated significant decreased tumor growth; this decrease was enhanced further with the addition of ABT-888. Decrease in tumor growth correlated with an increase in double strand DNA breaks as measured by γ-H2AX phosphorylation. In summary, inhibiting two arms of the DNA repair pathway simultaneously in TNBC cell lines, independent of BRCA mutation status, resulted in un-repairable DNA damage and subsequent cell death.
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spelling pubmed-43616402015-03-23 Protein Expression of DNA Damage Repair Proteins Dictates Response to Topoisomerase and PARP Inhibitors in Triple-Negative Breast Cancer Boerner, Julie L. Nechiporchik, Nicole Mueller, Kelly L. Polin, Lisa Heilbrun, Lance Boerner, Scott A. Zoratti, Gina L. Stark, Karri LoRusso, Patricia M. Burger, Angelika PLoS One Research Article Patients with metastatic triple-negative breast cancer (TNBC) have a poor prognosis. New approaches for the treatment of TNBC are needed to improve patient survival. The concept of synthetic lethality, brought about by inactivating complementary DNA repair pathways, has been proposed as a promising therapeutic option for these tumors. The TNBC tumor type has been associated with BRCA mutations, and inhibitors of Poly (ADP-ribose) polymerase (PARP), a family of proteins that facilitates DNA repair, have been shown to effectively kill BRCA defective tumors by preventing cells from repairing DNA damage, leading to a loss of cell viability and clonogenic survival. Here we present preclinical efficacy results of combining the PARP inhibitor, ABT-888, with CPT-11, a topoisomerase I inhibitor. CPT-11 binds to topoisomerase I at the replication fork, creating a bulky adduct that is recognized as damaged DNA. When DNA damage was stimulated with CPT-11, protein expression of the nucleotide excision repair enzyme ERCC1 inversely correlated with cell viability, but not clonogenic survival. However, 4 out of the 6 TNBC cells were synergistically responsive by cell viability and 5 out of the 6 TNBC cells were synergistically responsive by clonogenic survival to the combination of ABT-888 and CPT-11. In vivo, the BRCA mutant cell line MX-1 treated with CPT-11 alone demonstrated significant decreased tumor growth; this decrease was enhanced further with the addition of ABT-888. Decrease in tumor growth correlated with an increase in double strand DNA breaks as measured by γ-H2AX phosphorylation. In summary, inhibiting two arms of the DNA repair pathway simultaneously in TNBC cell lines, independent of BRCA mutation status, resulted in un-repairable DNA damage and subsequent cell death. Public Library of Science 2015-03-16 /pmc/articles/PMC4361640/ /pubmed/25774912 http://dx.doi.org/10.1371/journal.pone.0119614 Text en © 2015 Boerner et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Boerner, Julie L.
Nechiporchik, Nicole
Mueller, Kelly L.
Polin, Lisa
Heilbrun, Lance
Boerner, Scott A.
Zoratti, Gina L.
Stark, Karri
LoRusso, Patricia M.
Burger, Angelika
Protein Expression of DNA Damage Repair Proteins Dictates Response to Topoisomerase and PARP Inhibitors in Triple-Negative Breast Cancer
title Protein Expression of DNA Damage Repair Proteins Dictates Response to Topoisomerase and PARP Inhibitors in Triple-Negative Breast Cancer
title_full Protein Expression of DNA Damage Repair Proteins Dictates Response to Topoisomerase and PARP Inhibitors in Triple-Negative Breast Cancer
title_fullStr Protein Expression of DNA Damage Repair Proteins Dictates Response to Topoisomerase and PARP Inhibitors in Triple-Negative Breast Cancer
title_full_unstemmed Protein Expression of DNA Damage Repair Proteins Dictates Response to Topoisomerase and PARP Inhibitors in Triple-Negative Breast Cancer
title_short Protein Expression of DNA Damage Repair Proteins Dictates Response to Topoisomerase and PARP Inhibitors in Triple-Negative Breast Cancer
title_sort protein expression of dna damage repair proteins dictates response to topoisomerase and parp inhibitors in triple-negative breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361640/
https://www.ncbi.nlm.nih.gov/pubmed/25774912
http://dx.doi.org/10.1371/journal.pone.0119614
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