Abstract
Despite recent advances in the management of BRCA1 mutated high-grade serous ovarian cancer (HGSC), the physiology of these tumors remains poorly understood. Here we provide a comprehensive molecular understanding of the signaling processes that drive HGSC pathogenesis with the addition of valuable ubiquitination profiling, and their dependency on BRCA1 mutation-state directly in patient-derived tissues. Using a multilayered proteomic approach, we show the tight coordination between the ubiquitination and phosphorylation regulatory layers and their role in key cellular processes related to BRCA1-dependent HGSC pathogenesis. In addition, we identify key bridging proteins, kinase activity, and post-translational modifications responsible for molding distinct cancer phenotypes, thus providing new opportunities for therapeutic intervention, and ultimately advance towards a more personalized patient care.
Highlights
Despite recent advances in the management of BRCA1 mutated high-grade serous ovarian cancer (HGSC), the physiology of these tumors remains poorly understood
Gene ontology (GO) enrichment analysis revealed that while protein abundances were regulated in cellular processes involved in energy metabolism and translation (Fig. S2), phosphoproteome regulation mainly affected RNA splicing, cell cycle, DNA damage response, nucleosome components and proteins involved in cytoskeleton and cell junction organization
In this study we identified relevant molecular information related to the cellular physiological states of tumors and we provide relevant quantitative information of the ubiquitinome for the characterization of HGSC
Summary
Despite recent advances in the management of BRCA1 mutated high-grade serous ovarian cancer (HGSC), the physiology of these tumors remains poorly understood. Despite the advances made in vitro to decipher BRCA1 cellular functions, the importance of BRCA1 mutations in the clinical setting and the rapid escalation of the clinical use of PARP inhibitors, a deeper understanding of HGSC tumor molecular phenotypes is still necessary. This would allow the identification of new therapeutic targets in order to advance towards a more streamlined and personalized care. We highlight the importance of BRCA1 substrates in the modulation of HGSC ubiquitination events in vivo and the cellular compartmentalization of BRCA1-dependent signaling processes associated with pathogenic mutations
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