The Clinicopathological Significance of the Cyclin D1/E1–Cyclin-Dependent Kinase (CDK2/4/6)–Retinoblastoma (RB1/pRB1) Pathway in Epithelial Ovarian Cancers

Lashen, Ayat; Algethami, Mashael; Alqahtani, Shatha; Shoqafi, Ahmed; Sheha, Amera; Jeyapalan, Jennie N.; Mongan, Nigel P.; Rakha, Emad A.; Madhusudan, Srinivasan

Abstract

Cyclin-dependent kinases (CDK2, CDK4, CDK6), cyclin D1, cyclin E1 and phosphorylated retinoblastoma (pRB1) are key regulators of the G1/S cell cycle checkpoint and may influence platinum response in ovarian cancers. CDK2/4/6 inhibitors are emerging targets in ovarian cancer therapeutics. In the current study, we evaluated the prognostic and predictive significance of the CDK2/4/6–cyclin D1/E1–pRB1 axis in clinical ovarian cancers (OC). The CDK2/4/6, cyclin D1/E1 and RB1/pRB1 protein expression were investigated in 300 ovarian cancers and correlated with clinicopathological parameters and patient outcomes. CDK2/4/6, cyclin D1/E1 and RB1 mRNA expression were evaluated in the publicly available ovarian TCGA dataset. We observed nuclear and cytoplasmic staining for CDK2/4/6, cyclins D1/E1 and RB1/pRB1 in OCs with varying percentages. Increased nuclear CDK2 and nuclear cyclin E1 expression was linked with poor progression-free survival (PFS) and a shorter overall survival (OS). Nuclear CDK6 was associated with poor OS. The cytoplasmic expression of CDK4, cyclin D1 and cyclin E1 also has predictive and/or prognostic significance in OCs. In the multivariate analysis, nuclear cyclin E1 was an independent predictor of poor PFS. Tumours with high nuclear cyclin E1/high nuclear CDK2 have a worse PFS and OS. Detailed bioinformatics in the TCGA cohort showed a positive correlation between cyclin E1 and CDK2. We also showed that cyclin-E1-overexpressing tumours are enriched for genes involved in insulin signalling and release. Our data not only identified the prognostic/predictive significance of these key cell cycle regulators but also demonstrate the importance of sub-cellular localisation. CDK2 targeting in cyclin-E1-amplified OCs could be a rational approach.

Citation

Lashen, A., Algethami, M., Alqahtani, S., Shoqafi, A., Sheha, A., Jeyapalan, J. N., …Madhusudan, S. (2024). The Clinicopathological Significance of the Cyclin D1/E1–Cyclin-Dependent Kinase (CDK2/4/6)–Retinoblastoma (RB1/pRB1) Pathway in Epithelial Ovarian Cancers. International Journal of Molecular Sciences, 25(7), Article 4060. https://doi.org/10.3390/ijms25074060

• Journal Article Type: Article
• Acceptance Date: Apr 3, 2024
• Online Publication Date: Apr 5, 2024
• Publication Date: Apr 1, 2024
• Deposit Date: May 2, 2024
• Publicly Available Date: May 2, 2024
• Journal: International Journal of Molecular Sciences
• Print ISSN: 1661-6596
• Electronic ISSN: 1422-0067
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 25
• Issue: 7
• Article Number: 4060
• DOI: https://doi.org/10.3390/ijms25074060
• Keywords: CDK6, cyclin D, targeted therapy, ovarian cancer, cyclin E, Rb, CDK2, CDK4, prognostic biomarkers
• Public URL: https://nottingham-repository.worktribe.com/output/33294232
• Publisher URL: https://www.mdpi.com/1422-0067/25/7/4060