Collateral Sensitivity Associated with Multidrug-Resistance Protein 5 in Triple-Negative Breast Cancer

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aut.embargoNoen_NZ
aut.filerelease.date2025-04-12
aut.thirdpc.containsNoen_NZ
dc.contributor.advisorLi, Yan
dc.contributor.advisorLiu, Dong-Xu
dc.contributor.authorHe, Ji
dc.date.accessioned2022-04-11T23:39:27Z
dc.date.available2022-04-11T23:39:27Z
dc.date.copyright2022
dc.date.issued2022
dc.date.updated2022-04-11T05:30:37Z
dc.description.abstractThe multidrug resistance (MDR)-induced chemo- and targeted-therapeutic failure remains a pivotal obstacle to effective treatment against triple-negative breast cancer (TNBC). Our recent publications reviewed that the clinical trials that target ATP-Binding Cassette (ABC) transporters to reverse drug resistance have been disappointing despite the positive in vitro evidence. However, ABC transporters-associated collateral sensitivity (CS) is poorly understood and contributes to a promising novel therapeutic strategy to overcome MDR in breast cancer. In this study, we investigated olaparib accumulation and sensitivity in ABCC5-overexpressing HEK293 (HEK-MRP5) and ABCC5 gene knockout (KO) TNBC cell models. The potential upstream regulators of ABCC5 were also studied in the respective gene KO cell model. Overexpression of ABCC5 in HEK-MRP5 and TNBC cells (endogenously in MDA-MB-231 and BT549 cells) was associated with increased olaparib sensitivity. This vulnerability was not reversed by a model ABCC5 inhibitor benzbromarone. The low ABCC5 expression level in isogenic parental HEK293 and KO TNBC cells was associated with an olaparib-resistant phenotype. Molecular docking studies suggested non-covalent olaparib-ABCC5 interactions with high binding affinity. In conclusion, olaparib exerted selective CS on ABCC5-expressing BRAC1 wildtype TNBC cell lines (MDA-MB-231 and BT549) and these results may broaden the clinical indications of olaparib and/or lead to the novel combination therapies to resensitise tumour MDR in patients with TNBC.en_NZ
dc.identifier.urihttps://hdl.handle.net/10292/15055
dc.language.isoenen_NZ
dc.publisherAuckland University of Technology
dc.rights.accessrightsOpenAccess
dc.subjectCRISPR-Cas9en_NZ
dc.subjectTriple-negative breast canceren_NZ
dc.subjectTNBCen_NZ
dc.subjectolapariben_NZ
dc.subjectdoxorubicinen_NZ
dc.subjectcollateral sensitivityen_NZ
dc.subjectABCC5en_NZ
dc.subjectMRP5en_NZ
dc.subjectmultidrug-resistance protein 5en_NZ
dc.titleCollateral Sensitivity Associated with Multidrug-Resistance Protein 5 in Triple-Negative Breast Canceren_NZ
dc.typeThesisen_NZ
thesis.degree.grantorAuckland University of Technology
thesis.degree.levelDoctoral Theses
thesis.degree.nameDoctor of Philosophyen_NZ
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