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EP1117 Unravelling BRCA1-dependent molecular mechanisms in ovarian cancer by multi-level proteomics
  1. M Bradbury1,2,3,
  2. E. Borràs2,3,
  3. A Pérez-Benavente1,4,
  4. J De la Torre4,
  5. A Gil-Moreno1,4,
  6. E Sabidó2,3 and
  7. A Santamaria5
  1. 1Biomedical Research in Gynaecology, Vall d'Hebron Research Institute
  2. 2Proteomics Unit, Centre for Genomic Regulation
  3. 3University Pompeu Fabra
  4. 4Gynaecological Oncology Unit, Vall d'Hebron University Hospital
  5. 5Biomedical Research in Urology, Vall d'Hebron Research Institute, Barcelona, Spain

Abstract

Introduction/Background Our understanding of the molecular events associated to the development of high-grade serous ovarian cancer (HGSOC) in BRCA1 mutated patients and the differences observed in treatment response remain to be elucidated. Recent advances in large scale genomic analysis have shed a light on the importance of homologous recombination DNA repair and the beneficial use of PARP-inhibitor therapy. Nevertheless, additional cellular functions of BRCA1 in ovarian cancer are poorly understood.

Methodology We analysed thirty-two patient-derived fresh frozen tissues from healthy ovaries and chemotherapy-naïve advanced high-grade serous tumours by mass-spectometry based proteomics. BRCA1 mutation status was known for all patients (BRCA1mut and BRCA1wt). We quantitatively evaluated the protein changes and post-translational modifications focusing in the phosphorylation and ubiquitylation events. Comprehensive network analysis was performed comparing both healthy and cancer tissues based on their BRCA1 mutation status.

Results We identified a variety of differentially expressed proteins discriminating between cancer from healthy tissues predominantly related to cell cycle control, extracellular matrix organisation, mitochondrial translation and immunological response. Cancer tissues harvesting BRCA1mut showed specific changes related to DNA damage repair and activated mTOR and insulin signalling pathways. In addition, downregulation of active mRNA processing and RNA splicing proteins were also observed in BRCA1mut tumours.

Conclusion We demonstrate that direct patient tissue samples represent a valuable source for molecular investigation and provide new insights into the mechanisms of BRCA1 in ovarian cancer. We also highlight potential druggable target pathways in this group of patients. Finally, a deeper understanding of the RNA splicing events related to BRCA1 could unveil new clinically relevant cellular processes in ovarian cancer.

Disclosure Nothing to disclose

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