radART-Institute for Research and Development on Advanced Radiation Technologies, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
Department of Pathology, Paracelsus Medical University, SALK, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
Genes (Basel). 2020 Nov 26;11(12):1404. doi: 10.3390/genes11121404.
In order to characterize the various subtypes of breast cancer more precisely and improve patients selection for breast conserving therapy (BCT), molecular profiling has gained importance over the past two decades. MicroRNAs, which are small non-coding RNAs, can potentially regulate numerous downstream target molecules and thereby interfere in carcinogenesis and treatment response via multiple pathways. The aim of the current two-phase study was to investigate whether hsa-miR-375-signaling through RASD1 could predict local control (LC) in early breast cancer.
The patient and treatment characteristics of 81 individuals were similarly distributed between relapse ( = 27) and control groups ( = 54). In the pilot phase, the primary tumors of 28 patients were analyzed with microarray technology. Of the more than 70,000 genes on the chip, 104 potential hsa-miR-375 target molecules were found to have a lower expression level in relapse patients compared to controls (-value < 0.2). For RASD1, a hsa-miR-375 binding site was predicted by an in silico search in five mRNA-miRNA databases and mechanistically proven in previous pre-clinical studies. Its expression levels were markedly lower in relapse patients than in controls (-value of 0.058). In a second phase, this finding could be validated in an independent set of 53 patients using ddPCR. Patients with enhanced levels of hsa-miR-375 compared to RASD1 had a higher probability of local relapse than those with the inverse expression pattern of the two markers (log-rank test, -value = 0.069).
This two-phase study demonstrates that hsa-miR-375/RASD1 signaling is able to predict local control in early breast cancer patients, which-to our knowledge-is the first clinical report on a miR combined with one of its downstream target proteins predicting LC in breast cancer.
为了更精确地描述乳腺癌的各种亚型，并改善保乳治疗（BCT）患者的选择，分子谱分析在过去二十年中变得越来越重要。微小 RNA（miRNA）是小的非编码 RNA，可以潜在地调节众多下游靶分子，从而通过多种途径干扰癌变和治疗反应。本研究的目的是研究 hsa-miR-375 通过 RASD1 信号传导是否可以预测早期乳腺癌的局部控制（LC）。
81 例患者的患者和治疗特征在复发组（n=27）和对照组（n=54）之间相似分布。在初步阶段，对 28 例患者的原发性肿瘤进行了微阵列技术分析。在芯片上的 70,000 多个基因中，发现与对照组相比，复发组中有 104 个潜在的 hsa-miR-375 靶分子的表达水平较低（-值<0.2）。对于 RASD1，通过五个 mRNA-miRNA 数据库中的计算机搜索预测了 hsa-miR-375 的结合位点，并在以前的临床前研究中证明了其机制。与对照组相比，复发组中的 RASD1 表达水平明显较低（-值为 0.058）。在第二阶段，使用 ddPCR 在 53 例独立患者中验证了这一发现。与 RASD1 相比，hsa-miR-375 水平升高的患者发生局部复发的可能性高于两种标志物表达模式相反的患者（对数秩检验，-值=0.069）。
这项两阶段研究表明，hsa-miR-375/RASD1 信号能够预测早期乳腺癌患者的局部控制，这是第一个报告 miRNA 与其下游靶蛋白之一联合预测乳腺癌 LC 的临床报告。
