最近发现的人源lncRNA NORAD在p53依赖性方式下，在DNA损伤后被诱导表达。该lncRNA通过与Pumilio蛋白相互作用，在基因组稳定性的维持中起着关键作用，限制其靶向mRNA的抑制。因此，NORAD失活会导致染色体不稳定和非整倍体，从而促进遗传异常的积累和肿瘤发生。NORAD已在数种癌症中检测到，包括乳腺癌，这是最常见的和导致妇女癌症死亡的第二大原因。在本研究中，我们确认了一组人表皮乳腺癌细胞系（MDA-MB-231、MDA-MB-436和MDA-MB-468）中上调的NORAD表达水平，这些细胞系属于最具侵袭性的亚型（三阴性乳腺癌）。这些结果与先前的数据一致，高NORAD表达水平与基底样肿瘤的不良预后相关。此外，我们展示了NORAD 下调能增加三阴性乳腺癌细胞对化疗的敏感性，可能通过基因组异常的积累和受损的DNA损伤信号传导能力。这些结果表明，NORAD 可能代表一种未开发的新适应性靶向治疗靶点，适用于化疗无反应的乳腺癌。© 2023 The Author(s).

The recently discovered human lncRNA NORAD is induced after DNA damage in a p53-dependent manner. It plays a critical role in the maintenance of genomic stability through interaction with Pumilio proteins, limiting the repression of their target mRNAs. Therefore, NORAD inactivation causes chromosomal instability and aneuploidy, which contributes to the accumulation of genetic abnormalities and tumorigenesis. NORAD has been detected in several types of cancer, including breast cancer, which is the most frequently diagnosed and the second-leading cause of cancer death in women. In the present study, we confirmed upregulated NORAD expression levels in a set of human epithelial breast cancer cell lines (MDA-MB-231, MDA-MB-436, and MDA-MB-468), which belong to the most aggressive subtypes (triple-negative breast cancer). These results are in line with previous data showing that high NORAD expression levels in basal-like tumors were associated with poor prognosis. Here, we demonstrate that NORAD downregulation sensitizes triple-negative breast cancer cells to chemotherapy, through a potential accumulation of genomic aberrations and an impaired capacity to signal DNA damage. These results show that NORAD may represent an unexploited neoadjuvant therapeutic target for chemotherapy-unresponsive breast cancer.© 2023 The Author(s).