Our team is on break until January 7, 2026. Inquiries will be addressed shortly after our return. Thank you for your patience and happy holidays!
Repository logo
 

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

Files

Thesis(10.56 MB)

Date

2022

Authors

Supervisor

Li, Yan
Liu, Dong-Xu

Item type

Thesis

Degree name

Doctor of Philosophy

Journal Title

Journal ISSN

Volume Title

Publisher

Auckland University of Technology

Abstract

The 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.

Description

Keywords

CRISPR-Cas9, Triple-negative breast cancer, TNBC, olaparib, doxorubicin, collateral sensitivity, ABCC5, MRP5, multidrug-resistance protein 5

Source

DOI

Publisher's version

Rights statement

Permanent link

https://hdl.handle.net/10292/15055

Collections

Doctoral Theses