- Title
- Multiomic characterisation of cellular signalling regulated by PP2A-B55α in breast cancer and development
- Creator
- Chen, Yanfang
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2024
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Breast cancer is a leading cause of morbidity and mortality worldwide. Although progress has been made over the past few decades in early diagnosis and new treatments, disease progression and treatment resistance remain unresolved challenges. The PPP2R2A gene, which encodes the PP2A regulatory subunit B55α, is frequently deleted in breast tumours, and low expression of PP2A-B55α is associated with poor patient prognosis. Previous work from our laboratory has shown that molecular inhibition of PP2A-B55α in human breast cancer cells increases cell proliferation, migration and invasion, increases in vivo tumour growth, and induces resistance to therapy. However, the molecular mechanisms mediating these effects are not known. Therefore, the aim of this thesis was to investigate altered signalling pathways mediated by PP2A- B55α inhibition in breast cancer. Extensive analysis of B55α within the BT474 ER+/PR+/HER2+ cell line was undertaken by using lentiviral knockdown of B55α to generate two cell lines with different levels of B55α expression. The Proteome, Phosphoproteome and gene expression by RNA sequencing were all examined, and key signalling pathways identified in each is presented. Some of the key proteins identified were selected for further examination, including epethial to mesenchymal transition markers as well as components of the cytoskeleton. Of clinical importance, these analyses directed testing of numerous chemotherapies and it was discovered that reduced B55α expression induces resistance to CDK1 inhibitors and the YAP-1 inhibitor verteporfin, but some sensitivity to the microtubule destabilizing drug, vincristine. In addition to its role in tumour suppression, PP2A-B55α is an essential mediator of embryonic development. Our laboratory recently generated the first Ppp2r2a knockout mouse and found it to be embryonic lethal. To investigate the molecular mechanisms mediating this lethality full proteomics, phosphoproteomics and transcriptomics was performed with similar signalling pathways identified to those altered in the breast cancer cell lines. In summary, the work contained in this thesis demonstrates that PP2A-B55α is an important regulator of multiple growth, survival and differentiation pathways. The findings not only increase our understanding of how B55α inhibition mediates breast tumourigenesis and embryonic development, but also uncovered potential tumour biomarkers that could improve treatment stratification in breast cancer patients and identified potential new therapeutic targets.
- Subject
- breast cancer; phosphoproteome; PP2A-B55α; tumor
- Identifier
- http://hdl.handle.net/1959.13/1497185
- Identifier
- uon:54307
- Rights
- This thesis is currently under embargo and will be available from 19.01.2025, Copyright 2024 Yanfang Chen
- Language
- eng
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- Visitors: 1876
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