Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany.
Department of Bioinformatics, Semmelweis University, Budapest, Hungary.
J Cell Biochem. 2022 Mar;123(3):581-600. doi: 10.1002/jcb.30205. Epub 2022 Jan 10.
Breast cancer is the third most common type of cancer diagnosed. Cell cycle is a complex but highly organized and controlled process, in which normal cells sense mitogenic growth signals that instruct them to enter and progress through their cell cycle. This process culminates in cell division generating two daughter cells with identical amounts of genetic material. Uncontrolled proliferation is one of the hallmarks of cancer. In this study, we analyzed the expression of the cell cycle-related genes receptor for hyaluronan (HA)-mediated motility (RHAMM), AURKA, TPX2, PLK1, and PLK4 and correlated them with the prognosis in a collective of 3952 breast cancer patients. A high messenger RNA expression of all studied genes correlated with a poor prognosis. Stratifying the patients according to the expression of hormonal receptors, we found that in patients with estrogen and progesterone receptor-positive and human epithelial growth factor receptor 2-negative tumors, and Luminal A and Luminal B tumors, the expression of the five analyzed genes correlates with worse survival. qPCR analysis of a panel of breast cancer cell lines representative of major molecular subtypes indicated a predominant expression in the luminal subtype. In vitro experiments showed that radiation influences the expression of the five analyzed genes both in luminal and triple-negative model cell lines. Functional analysis of MDA-MB-231 cells showed that small interfering RNA knockdown of PLK4 and TPX2 and pharmacological inhibition of PLK1 had an impact on the cell cycle and colony formation. Looking for a potential upstream regulation by microRNAs, we observed a differential expression of RHAMM, AURKA, TPX2, PLK1, and PLK4 after transfecting the MDA-MB-231 cells with three different microRNAs. Survival analysis of miR-34c-5p, miR-375, and miR-142-3p showed a different impact on the prognosis of breast cancer patients. Our study suggests that RHAMM, AURKA, TPX2, PLK1, and PLK4 can be used as potential targets for treatment or as a prognostic value in breast cancer patients.
乳腺癌是诊断出的第三常见癌症类型。细胞周期是一个复杂但高度组织和控制的过程，其中正常细胞感知有丝分裂生长信号，指示它们进入并通过细胞周期进行。这个过程最终导致细胞分裂，产生两个具有相同遗传物质量的子细胞。不受控制的增殖是癌症的一个标志。在这项研究中，我们分析了细胞周期相关基因受体透明质酸（HA）介导的运动（RHAMM）、AURKA、TPX2、PLK1 和 PLK4 的表达，并将其与 3952 名乳腺癌患者的预后相关联。所有研究基因的高信使 RNA 表达与预后不良相关。根据激素受体的表达对患者进行分层，我们发现，在雌激素和孕激素受体阳性、人类表皮生长因子受体 2 阴性肿瘤以及 Luminal A 和 Luminal B 肿瘤的患者中，五种分析基因的表达与生存较差相关。对一组代表主要分子亚型的乳腺癌细胞系的 qPCR 分析表明，这些基因在 luminal 亚型中表达占主导地位。体外实验表明，辐射对 luminal 和三阴性模型细胞系中五种分析基因的表达都有影响。MDA-MB-231 细胞的功能分析表明，PLK4 和 TPX2 的小干扰 RNA 敲低和 PLK1 的药理学抑制对细胞周期和集落形成有影响。为了寻找潜在的 miRNA 上游调控，我们观察到在转染 MDA-MB-231 细胞后，RHAMM、AURKA、TPX2、PLK1 和 PLK4 的表达有差异。miR-34c-5p、miR-375 和 miR-142-3p 的生存分析显示对乳腺癌患者预后有不同的影响。我们的研究表明，RHAMM、AURKA、TPX2、PLK1 和 PLK4 可用作乳腺癌患者治疗的潜在靶点或作为预后价值。
