已知导致 microRNA (miRNA/miR) 差异表达的表观遗传改变可调节肿瘤细胞状态、上皮间质转化 (EMT) 和乳腺癌转移的进展。本研究探讨了 miRNA-18a 在介导混合 E/M 细胞状态中的关键贡献，这种状态对于侵袭性 ER 阴性乳腺癌亚型的恶性转化和肿瘤进展至关重要。结合公共数据集中的基因表达数据，在患者来源的乳腺肿瘤样本中评估了 miR-18a 的表达状态和相关效应，并在体外和体内乳腺癌模型系统中进一步验证。研究结果的临床相关性得到了人类乳腺肿瘤标本（n = 446 名患者）的证实。研究发现，在 ER 阴性肿瘤中观察到的 miR-18a 表达下调可促进混合上皮/间质 (E/M) 细胞的富集，这些细胞具有管腔属性、增强的迁移特性、干性、耐药性和免疫抑制。对 miR-18a 靶标的进一步分析强调了这些肿瘤中可能存在缺氧诱导因子 1-α (HIF-1α) 介导的信号传导。这是一份最重要的报告，验证了 miR-18a 在乳腺癌中的双重作用，即基于激素受体表达的亚型特异性。该研究还提出了低 miR-18a 水平与随后杂合 E/M 细胞富集、ER 阴性肿瘤亚组迁移和干性增加之间的新关联，这可能归因于 HIF-1α 介导的信号传导。结果强调了通过分析 miRNA 特征将 ER 阴性疾病分层为临床相关组的可能性。

Epigenetic alterations that lead to differential expression of microRNAs (miRNAs/miR) are known to regulate tumour cell states, epithelial-mesenchymal transition (EMT) and the progression to metastasis in breast cancer. This study explores the key contribution of miRNA-18a in mediating a hybrid E/M cell state that is pivotal to the malignant transformation and tumour progression in the aggressive ER-negative subtype of breast cancer. The expression status and associated effects of miR-18a were evaluated in patient-derived breast tumour samples in combination with gene expression data from public datasets, and further validated in in vitro and in vivo breast cancer model systems. The clinical relevance of the study findings was corroborated against human breast tumour specimens (n = 446 patients). The down-regulated expression of miR-18a observed in ER-negative tumours was found to drive the enrichment of hybrid epithelial/mesenchymal (E/M) cells with luminal attributes, enhanced traits of migration, stemness, drug-resistance and immunosuppression. Further analysis of the miR-18a targets highlighted possible hypoxia-inducible factor 1-alpha (HIF-1α)-mediated signalling in these tumours. This is a foremost report that validates the dual role of miR-18a in breast cancer that is subtype-specific based on hormone receptor expression. The study also features a novel association of low miR-18a levels and subsequent enrichment of hybrid E/M cells, increased migration and stemness in a subgroup of ER-negative tumours that may be attributed to HIF-1α mediated signalling. The results highlight the possibility of stratifying the ER-negative disease into clinically relevant groups by analysing miRNA signatures.