Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham NG7 3RD, UK.
Department of Pathology, Nottingham University Hospital, City Campus, Nottingham NG5 1PB, UK.
Int J Mol Sci. 2024 May 6;25(9):5053. doi: 10.3390/ijms25095053.
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 ( = 1980) and TCGA cohort ( = 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 -values < 0.0001), and shorter survival ( = 0.006), especially in luminal BC ( = 0.009). In p53-mutant BC, high nuclear CDK2 remained linked with worse survival ( = 0.01). In DCIS, high nuclear/low cytoplasmic co-expression showed significant association with a high tumour grade ( = 0.043), triple-negative and HER2-enriched molecular subtypes ( = 0.01), Comedo necrosis ( = 0.024), negative ER status ( = 0.004), negative PR status ( < 0.0001), and a high proliferation index ( < 0.0001). Tumours with high 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.
细胞周期蛋白依赖性激酶 2（CDK2）是一种关键的细胞周期调节剂，在 G1/S 转换过程中具有重要作用。CDK2 在导管原位癌（DCIS）和早期浸润性乳腺癌（BC）中的临床病理意义在很大程度上尚不清楚。在这里，我们评估了 479 例 BC 样本和 216 例 DCIS 标本中 CDK2 的蛋白表达。分别在 METABRIC 队列（=1980）和 TCGA 队列（=1090）中分析了 CDK2 转录本。高核 CDK2 蛋白表达与侵袭性表型显著相关，包括高肿瘤分级、淋巴血管侵犯、不良 Nottingham 预后指数（所有 - 值<0.0001）和较短的生存时间（=0.006），尤其是在 luminal BC 中（=0.009）。在 p53 突变型 BC 中，高核 CDK2 仍然与较差的生存时间相关（=0.01）。在 DCIS 中，高核/低细胞质共表达与高肿瘤分级（=0.043）、三阴性和 HER2 富集的分子亚型（=0.01）、粉刺样坏死（=0.024）、阴性 ER 状态（=0.004）、阴性 PR 状态（<0.0001）和高增殖指数（<0.0001）显著相关。高 转录物的肿瘤更可能具有更高的参与细胞周期、同源重组和 p53 信号通路的基因表达。我们提供了令人信服的证据表明，高 CDK2 是侵袭性乳腺癌的特征。CDK2 抑制剂在早期 BC 患者中的临床评估将具有临床影响。
