{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T16:16:10Z","timestamp":1772208970762,"version":"3.50.1"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T00:00:00Z","timestamp":1609977600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA228083"],"award-info":[{"award-number":["CA228083"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003008","name":"Ministry of Higher Education, Egypt","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003008","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Triple negative breast cancer (TNBC) represents approximately 10\u201315% 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\n                    <jats:italic>BRCA1<\/jats:italic>\n                    . Poly (ADP-ribose) polymerase inhibitor (PARPi) drugs have demonstrated some effectiveness in treating\n                    <jats:italic>BRCA1<\/jats:italic>\n                    or\n                    <jats:italic>BRCA2<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0235025","type":"journal-article","created":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T19:25:31Z","timestamp":1610047531000},"page":"e0235025","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells"],"prefix":"10.1371","volume":"16","author":[{"given":"Dina","family":"Moustafa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maha R. Abd","family":"Elwahed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanaa H.","family":"Elsaid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5616-1928","authenticated-orcid":true,"given":"Jeffrey D.","family":"Parvin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,1,7]]},"reference":[{"issue":"26","key":"pone.0235025.ref001","doi-asserted-by":"crossref","first-page":"4282","DOI":"10.1200\/JCO.2008.16.6231","article-title":"Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer","volume":"26","author":"DP Atchley","year":"2008","journal-title":"Journal of Clinical Oncology"},{"issue":"4","key":"pone.0235025.ref002","first-page":"215","article-title":"PARP inhibitors: Review of mechanisms of action and BRCA1\/2 mutation targeting","volume":"15","author":"KN Dziadkowiec","year":"2016","journal-title":"Przeglad Menopauzalny."},{"issue":"7035","key":"pone.0235025.ref003","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nature03445","article-title":"Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy","volume":"434","author":"H Farmer","year":"2005","journal-title":"Nature"},{"issue":"7035","key":"pone.0235025.ref004","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/nature03443","article-title":"Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase","volume":"434","author":"HE Bryant","year":"2005","journal-title":"Nature"},{"issue":"4","key":"pone.0235025.ref005","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nrc2812","article-title":"Poirier GG. 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