Date of Award

11-4-2024

Degree Type

Thesis

Degree Name

MPhil in Biological and Biomedical Sciences

First Advisor

Dr Kulsoom Ghias

Second Advisor

Dr Sheerien Rajput

Third Advisor

Dr Azhar Hussain

Department

Biological and Biomedical Sciences

Abstract

Breast cancer (BCa) is amongs the major cause of mortalities and morbidity in women globally. Triple negative breast cancer (TNBC) is known for its aggressive nature and is associated with high recurrence and metastasis with poor overall survival; 50% of the patients relapse in the first three years. Despite efforts to identify potential therapeutic agents to improve the overall survival of TNBC patients, drug resistance tends to develop in the majority of cases. The reasons for drug resistance are complex and involve dysregulation of different cell signaling pathways, such as Wnt/β-catenin, NFκB and PI3K/AKT. This study explored the role of Wnt/β-catenin, NFκB and PI3K/AKT survival pathways in Oxaliplatin-resistant TNBC cell line. Oxaliplatin-resistant clones were developed in the TNBC cell line MDA-MB-231, by treating them with oxaliplatin doses of 2 and 4µM. Differential gene expressions between chemo-resistant clones and parental cells revealed the dysregulation of resistance-related genes, such as at 4µM treatment CD44 (p< 0.001), COX-2 (p < 0.001), ABCG2, BCL-2 (p < 0.05) and BAX (p < 0.01), alongside a shift towards a mesenchymal phenotype in resistant clones. Signaling pathways were altered, such as the upregulation of β-catenin in the Wnt/β-catenin pathway, Rel-A and NFκB1 in the NFκB pathway, and differential expression of AKT1 and PTEN in the PI3K/Akt pathway. Additionally, resistant clones displayed G2/M cell cycle arrest. The findings of the study enhanced our understanding of drug resistance mechanisms in triple-negative breast cancer (TNBC) and identify possible targets for therapy.

First Page

1

Last Page

81

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