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oai:figshare.com:article/32805218 2026-10-01T16:17:25Z portal_1172 item_type_8 month_year_10_2026

COPZ1 as a therapeutic target in triple-negative breast cancer: pharmacological and molecular approaches Remaa Alhusban (24292559) PUREID: 668530152 COPZ1 personalised medicine developing biomarker therapeutic potential RALA peptide nanomedicine synthetic lethality Triple Negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer, accounting for approximately 15-20% of all cases yet contributing to nearly 40% of breast cancer-related deaths. These tumours are characterised by the absence of oestrogen receptor (ER), progesterone receptor (PR) and HER2 amplification, meaning they do not benefit from targeted endocrine or HER2-directed therapies. Therefore, chemotherapy remains the mainstay of treatment; however, patient responses vary. The absence of reliable biomarkers to predict therapeutic response and the lack of actionable molecular targets for non-responders remain major clinical challenges. Therefore, identifying new biomarkers and therapeutic vulnerabilities is crucial for improving outcomes in TNBC patients. <br><br>This research project explores the role of the Coatomer protein complex zeta I (COPZ1) in TNBC, as it emerged as part of a gene signature associated with poor outcome following anthracycline-based chemotherapy in an in-house microarray dataset. Bioinformatic analyses confirmed that high COPZ1 expression was linked significantly to unfavourable outcome and therapeutic resistance, suggesting a functional role in tumour progression. Functional and transcriptomic analyses further revealed that COPZ1 defines two distinct TNBC states: tumours with high COPZ1 expression exhibited enhanced DNA repair, oxidative phosphorylation and proliferative programmes that likely underpin the observed anthracycline resistance, whereas tumours with low COPZ1 displayed immune activation signatures and relative sensitivity to taxanes, warranting further investigation. Experimental depletion through in vitro and genomic functional screening of COPZ1 further confirmed its context-dependent essentiality; a subset of TNBC models was highly sensitive to its loss, while others were tolerant, reflecting biological heterogeneity beyond expression levels and the influence of the well-known COPZ1 and COPZ2 synthetic lethality.<br><br>To evaluate its therapeutic potential, COPZ1 silencing was pursued using the bio-inspired nanocarrier RALA as a non-viral delivery system. These nanoparticles displayed optimal physicochemical properties with minimal cytotoxicity in vitro, achieving effective COPZ1 knockdown and reduced cell viability. However, in vivo application in the highly aggressive 4T1 TNBC models revealed limited efficacy, possibly due to rapid siRNA clearance and incomplete tumour penetration. Overall, this research establishes COPZ1 as a context-dependent vulnerability in TNBC, linking its upregulation to anthracycline resistance through enhanced DNA repair and metabolic reprogramming, while highlighting both the promise and translational challenges of RNAi-based approaches for targeting this pathway. <br><br><i>Thesis is embargoed until 31 July 2031.</i> 2026-10-01T16:17:25Z Text Thesis 10.17034/32805218.v1 https://figshare.com/articles/thesis/COPZ1_as_a_therapeutic_target_in_triple-negative_breast_cancer_pharmacological_and_molecular_approaches/32805218 All Rights Reserved Open Access after 2031-07-31