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.

Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator, with essential roles during G1/S transition. The clinicopathological significance of CDK2 in ductal carcinomas in situ (DCIS) and early-stage invasive breast cancers (BCs) remains largely unknown. Here, we evaluated CDK2’s protein expression in 479 BC samples and 216 DCIS specimens. Analysis of CDK2 transcripts was completed in the METABRIC cohort (n = 1980) and TCGA cohort (n = 1090), respectively. A high nuclear CDK2 protein expression was significantly associated with aggressive phenotypes, including a high tumour grade, lymph vascular invasion, a poor Nottingham prognostic index (all p-values < 0.0001), and shorter survival (p = 0.006), especially in luminal BC (p = 0.009). In p53-mutant BC, high nuclear CDK2 remained linked with worse survival (p = 0.01). In DCIS, high nuclear/low cytoplasmic co-expression showed significant association with a high tumour grade (p = 0.043), triple-negative and HER2-enriched molecular subtypes (p = 0.01), Comedo necrosis (p = 0.024), negative ER status (p = 0.004), negative PR status (p < 0.0001), and a high proliferation index (p < 0.0001). Tumours with high CDK2 transcripts were more likely to have higher expressions of genes involved in the cell cycle, homologous recombination, and p53 signaling. We provide compelling evidence that high CDK2 is a feature of aggressive breast cancers. The clinical evaluation of CDK2 inhibitors in early-stage BC patients will have a clinical impact.

Resistance to platinum-based chemotherapy is a major clinical problem in ovarian cancers. The development of predictive biomarkers and therapeutic approaches is an area of unmet need. p73, a member of the p53 family of transcription factors, has essential functions during DNA repair, proliferation, invasion, and apoptosis. The role of p73 in ovarian cancer pathogenesis and response to therapy is largely unknown. The clinicopathological significance of p73 protein expression was evaluated in 278 human ovarian cancers. TP73 transcripts were investigated in publicly available clinical data sets (n = 522) and bioinformatics analysis was completed in the ovarian TCGA cohort (n = 182). Preclinically, p73 was overexpressed in A2780 platinum-sensitive ovarian cancer cells or depleted in platinum-resistant A2780cis cells and investigated for aggressive phenotypes, as well as platinum sensitivity. High p73 protein expression was linked with high grade (p < 0.001), advanced-stage disease (p = 0.002), and shorter progression-free survival (p < 0.0001). TP73 transcripts were significantly higher in tumours compared to normal tissue (p < 0.0001) and linked with shorter PFS (p = 0.047). Preclinically, p73 overexpression in A2780 cells increased proliferation, invasion, spheroid formation, and DNA repair capacity, and was associated with the upregulation of multiple DNA repair and platinum resistance-associated genes. In contrast, p73 deletion in A2780cis led to reduced proliferation and enhanced sensitivity to cisplatin, along with DNA double-strand break accumulation, G2/M cell cycle arrest, and increased apoptosis. We conclude that p73 is a predictor of platinum resistance. p73 can be exploited for targeted ovarian cancer therapy.

Breast cancer (BC), which remains the most prevalent malignancy among women, is characterised by significant heterogeneity across its molecular subtypes. Oestrogen receptor-positive (ER+) (luminal) BC represents approximately 75% of cases, and despite advancements in treatment there remains around a 40% recurrence rate. Cellular uptake of glutamine is conducted by solute carriers (SLCs), which are significantly associated with outcome in luminal BC. In this study, differential gene expression analysis was carried out using The Cancer Genome Atlas BC dataset. This identified hydroxyacid oxidase 1 (HAO1) as significantly overexpressed in luminal BC with a high expression of SLCs. Extended analysis in the METABRIC (n = 1980) and Breast Cancer Gene-Expression Miner (n = 4421) transcriptomic databases and the Nottingham (n = 952) BC tissue cohort showed a varied survival outcome for HAO1 expression at the genomic, transcriptomic, and proteomic levels. HAO1 copy number (CN) gain (p = 0.002) and high HAO1 protein expression (p = 0.019) were associated with poor prognosis in luminal BC, whereas high HAO1 mRNA expression correlated with better survival outcomes (p = 0.023) suggesting a complex regulatory mechanism affecting HAO1 at different biological levels. Importantly, in luminal BC patients treated with endocrine therapy, high protein expression of HAO1 predicted shorter distant-metastasis free survival (p = 0.042). The knockdown of SLC1A5 and SLC7A5 significantly reduced HAO1 expression in MCF-7 and ZR-751 BC cell lines. Protein analysis confirmed significant associations between HAO1 and SLC7A5 and SLC1A5, emphasising a potential role for the enzyme in glutamine metabolism and its potential as a therapeutic target. This study underscores the prognostic significance of HAO1 in luminal BC and its relationship with patient outcomes.