Novel therapies targeting N-WASP protein in breast cancer

Yu, Yannan 2025. Novel therapies targeting N-WASP protein in breast cancer. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Metastasis remains the number one cause of death for breast cancer and particularly for aggressive forms such as triple-negative breast cancer (TNBC), for which there are extremely limited treatment options. In this thesis, I investigate the role of Neural WiskottAldrich Syndrome Protein (N-WASP), which is a key regulator of actin cytoskeleton dynamics and which is significant for tumour cell invasion and migration, and its potential as an exciting new therapeutic target for suppressing metastatic progression. A focused screening strategy was adopted to identify novel small-molecule inhibitors(E06, F02, F04, F06) and repurposed clinically viable compounds (Rucaparib, Aerius, Cyproheptadine) against N-WASP-mediated actin polymerisation. Functional assays verified that these inhibitors heavily suppressed breast cancer and endothelial cell proliferation, migration, and invasive phenotypes, and compound F06 exhibited extremely potent and persistent anti-metastatic activities. Direct biochemical validation using pyrene-actin polymerisation assays confirmed that selected inhibitors, notably F06, specifically disrupted N-WASP-Arp2/3-mediated actin filament nucleation. Proteomic and phosphoproteomic analyses using mass spectrometry further revealed extensive alterations in actin-binding proteins, adhesion complexes, and signalling intermediates following N-WASP inhibition in MDA-MB-231 cells. Integrated network analyses (STRING) and pathway enrichment (Reactome) provided detailed mechanistic insights consistent with results observed in N-WASP genetic knockdown models. Overall, this thesis demonstrates that N-WASP critically drives invasive behaviours in breast cancer, particularly in TNBC, and highlights the therapeutic potential of both novel and repurposed N-WASP inhibitors. These findings offer a substantial basis for future development of targeted anti-metastatic strategies and clinical translation in breast cancer management.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	25 November 2025
Last Modified:	26 Nov 2025 12:03
URI:	https://orca.cardiff.ac.uk/id/eprint/182562

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