Cargando…

Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells

Triple negative breast cancer (TNBC) represents approximately 10–15% of all breast cancers and has a poor outcome as it lacks a receptor target for therapy, and TNBC is frequently associated with a germline mutation of BRCA1. Poly (ADP-ribose) polymerase inhibitor (PARPi) drugs have demonstrated som...

Descripción completa

Detalles Bibliográficos
Autores principales: Moustafa, Dina, Elwahed, Maha R. Abd, Elsaid, Hanaa H., Parvin, Jeffrey D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790533/
https://www.ncbi.nlm.nih.gov/pubmed/33412559
http://dx.doi.org/10.1371/journal.pone.0235025
_version_ 1783633444447715328
author Moustafa, Dina
Elwahed, Maha R. Abd
Elsaid, Hanaa H.
Parvin, Jeffrey D.
author_facet Moustafa, Dina
Elwahed, Maha R. Abd
Elsaid, Hanaa H.
Parvin, Jeffrey D.
author_sort Moustafa, Dina
collection PubMed
description Triple negative breast cancer (TNBC) represents approximately 10–15% of all breast cancers and has a poor outcome as it lacks a receptor target for therapy, and TNBC is frequently associated with a germline mutation of BRCA1. Poly (ADP-ribose) polymerase inhibitor (PARPi) drugs have demonstrated some effectiveness in treating BRCA1 or BRCA2 mutated breast and ovarian cancers but resistance to PARPi is common. Published results found that resistance to Olaparib, a PARPi, can be due to downregulation of EMI1 and the consequent upregulation of the RAD51 recombinase. Using a tissue culture-based cell viability assay, we extended those observations to another PARPi and to other chemotherapy drugs that affect DNA repair or the cell cycle. As we expected, EMI1 downregulation resulted in resistance to another PARPi drug, Talazoparib. EMI1 downregulation also led to resistance to other cytotoxic drugs, Cisplatin and CHK1 inhibitor. Notably, increasing the RAD51 protein expression only recapitulated some, but not all, of the effects of EMI1 depletion in conferring to the cell resistance to different PARPi and the other cytotoxic drugs. These results suggest that the downstream effects of EMI1 downregulation that contribute to PARPi resistance are increasing the concentration of RAD51 protein in the cell and blocking mitotic entry. We found that combining CHK1 inhibitor with olaparib results in restoration of sensitivity even when EMI1 expression is downregulated. This combination therapy may be a means to overcome the PARPi resistance in BRCA1-deficient TNBC cells.
format Online
Article
Text
id pubmed-7790533
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-77905332021-01-27 Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells Moustafa, Dina Elwahed, Maha R. Abd Elsaid, Hanaa H. Parvin, Jeffrey D. PLoS One Research Article Triple negative breast cancer (TNBC) represents approximately 10–15% of all breast cancers and has a poor outcome as it lacks a receptor target for therapy, and TNBC is frequently associated with a germline mutation of BRCA1. Poly (ADP-ribose) polymerase inhibitor (PARPi) drugs have demonstrated some effectiveness in treating BRCA1 or BRCA2 mutated breast and ovarian cancers but resistance to PARPi is common. Published results found that resistance to Olaparib, a PARPi, can be due to downregulation of EMI1 and the consequent upregulation of the RAD51 recombinase. Using a tissue culture-based cell viability assay, we extended those observations to another PARPi and to other chemotherapy drugs that affect DNA repair or the cell cycle. As we expected, EMI1 downregulation resulted in resistance to another PARPi drug, Talazoparib. EMI1 downregulation also led to resistance to other cytotoxic drugs, Cisplatin and CHK1 inhibitor. Notably, increasing the RAD51 protein expression only recapitulated some, but not all, of the effects of EMI1 depletion in conferring to the cell resistance to different PARPi and the other cytotoxic drugs. These results suggest that the downstream effects of EMI1 downregulation that contribute to PARPi resistance are increasing the concentration of RAD51 protein in the cell and blocking mitotic entry. We found that combining CHK1 inhibitor with olaparib results in restoration of sensitivity even when EMI1 expression is downregulated. This combination therapy may be a means to overcome the PARPi resistance in BRCA1-deficient TNBC cells. Public Library of Science 2021-01-07 /pmc/articles/PMC7790533/ /pubmed/33412559 http://dx.doi.org/10.1371/journal.pone.0235025 Text en © 2021 Moustafa 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Moustafa, Dina
Elwahed, Maha R. Abd
Elsaid, Hanaa H.
Parvin, Jeffrey D.
Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells
title Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells
title_full Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells
title_fullStr Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells
title_full_unstemmed Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells
title_short Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells
title_sort modulation of early mitotic inhibitor 1 (emi1) depletion on the sensitivity of parp inhibitors in brca1 mutated triple-negative breast cancer cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790533/
https://www.ncbi.nlm.nih.gov/pubmed/33412559
http://dx.doi.org/10.1371/journal.pone.0235025
work_keys_str_mv AT moustafadina modulationofearlymitoticinhibitor1emi1depletiononthesensitivityofparpinhibitorsinbrca1mutatedtriplenegativebreastcancercells
AT elwahedmaharabd modulationofearlymitoticinhibitor1emi1depletiononthesensitivityofparpinhibitorsinbrca1mutatedtriplenegativebreastcancercells
AT elsaidhanaah modulationofearlymitoticinhibitor1emi1depletiononthesensitivityofparpinhibitorsinbrca1mutatedtriplenegativebreastcancercells
AT parvinjeffreyd modulationofearlymitoticinhibitor1emi1depletiononthesensitivityofparpinhibitorsinbrca1mutatedtriplenegativebreastcancercells