MicroRNAs (miRNAs) are small noncoding RNAs that act as endogenous regulatory molecules targeting specific mRNAs for translational repression. Studies of breast cancer genomics indicate that breast cancer subtypes are distinguished and regulated by specific sets of miRNAs which affect activities such as tumor initiation, progression, and even drug response. Polo-like Kinase 1 (PLK1) is widely considered to be a proto-oncogene due to its increased expression in multiple tumor types, as well as its crucial role in regulating mitosis. Pharmacological inhibition of PLK1 can reduce tumor volume and induce tumor cell death in solid and hematologic malignancies. This prompted us to investigate how PLK1 inhibition with the target-specific inhibitor NMS-P937 would impact breast cancer cells, and how miRNAs may influence the overall response of these cells to this inhibition. We found that miR-183-5p targets PLK1 gene, effectively reducing its protein expression. Such miRNA-driven regulation of PLK1 expression sensitizes breast cancer cells to NMS-P937, resulting in synergistically increased apoptosis. We also show that the miRNA-regulated reduction of PLK1 influences the expression of apoptosis-related key proteins and possibly inducing further indirect PLK1 downmodulation through a DNMT1-p53 axis. These results suggest a potential biologically significant link between the expression of miR-183-5p and the efficacy of PLK1-specific inhibitors in breast cancer cells. Our work further elucidates how miR-183-5p regulates PLK1 gene while also enhancing NMS-P937 effect in breast cancer. Future studies assessing the role of miR-183-5p as a novel biomarker for anti-PLK1 chemotherapy agents are warranted.

微小 RNA (miRNA) 是小的非编码 RNA，可作为内源性调节分子靶向特定 mRNA 进行翻译抑制。乳腺癌基因组学研究表明，乳腺癌亚型由特定的 miRNA 组区分和调节，这些 miRNA 影响诸如肿瘤起始、进展甚至药物反应等活动。Polo 样激酶 1 (PLK1) 被广泛认为是一种原癌基因，因为它在多种肿瘤类型中表达增加，并且在调节有丝分裂中起着至关重要的作用。PLK1 的药理学抑制可以减少肿瘤体积并诱导实体和血液恶性肿瘤中的肿瘤细胞死亡。这促使我们研究用靶标特异性抑制剂 NMS-P937 抑制 PLK1 将如何影响乳腺癌细胞，以及 miRNA 如何影响这些细胞对这种抑制的整体反应。我们发现 miR-183-5p 靶向 PLK1 基因，有效降低其蛋白表达。这种 miRNA 驱动的 PLK1 表达调节使乳腺癌细胞对 NMS-P937 敏感，从而协同增加细胞凋亡。我们还表明，miRNA 调节的 PLK1 减少影响细胞凋亡相关关键蛋白的表达，并可能通过 DNMT1-p53 轴进一步间接诱导 PLK1 下调。这些结果表明 miR-183-5p 的表达与 PLK1 特异性抑制剂在乳腺癌细胞中的功效之间存在潜在的生物学显着联系。我们的工作进一步阐明了 miR-183-5p 如何调节 PLK1 基因，同时增强 NMS-P937 在乳腺癌中的作用。