Ordonez, LilianaAlmuafi, Mashael2024-11-282024-07https://hdl.handle.net/20.500.14154/73882Introduction Breast cancer ranks as the most frequently occurring cancer in the UK. Although there have been promising advancements in survival rates, it remains the second leading cause of cancer-related death among women in the UK. BRCA2 mutations predispose individuals to breast cancer and affect DNA repair mechanisms. While targeted therapies such as olaparib (PARP inhibitors) and carboplatin (platinum-based chemotherapies) have shown efficacy, resistance remains a significant challenge. This study aims to investigate the mechanisms underlying resistance to carboplatin and olaparib in BRCA2-mutated breast cancer, focusing on epithelial-mesenchymal transition (EMT) as a potential pathway contributing to therapy resistance. Methods Using a previously genetically engineered mouse model with BRCA2/TP53 mutations, tumour samples were analysed using hematoxylin and eosin (H&E) for morphological characteristics and expression of key markers (E-cadherin, vimentin, Ki67) via immunohistochemistry (IHC). Tumours were categorised into untreated, olaparib-resistant and carboplatin-resistant groups. Statistical analysis was performed to compare marker expression and morphological features across these groups. Results H&E analysis revealed interestingly that carboplatin-resistant tumours showed an equal distribution of epithelial and mesenchymal features, not significantly different from untreated and Olaparib-resistant tumours. IHC analysis of EMT markers showed that carboplatin-resistant tumours maintained moderate E-cadherin levels. Vimentin expression showed no significant differences in carboplatin-resistant tumours compared to untreated and Olaparib-resistant tumours. Notably, Ki67 expression analysis revealed no significant differences in proliferation rates across all three cohorts, challenging the assumption that resistant tumours would exhibit increased proliferation. These findings suggest distinct resistance mechanisms between olaparib and carboplatin in BRCA2-mutated breast cancer. EMT appears to play a crucial role in olaparib-resistance but not in carboplatin-resistance. These findings underscore the need for tailored treatment strategies and further research into the diverse mechanisms of therapy resistance. Future studies should focus on developing EMT-targeted therapies and exploring their efficacy in combination with existing treatments to improve patient outcomes.46en-USBreast CancerBRCA2BRCA1ChemotherapycarboplatinolaoaribThesis