Approximately 25% of breast cancer (BC) patients are HER2-positive. Trastuzumab is used as a targeted therapy drug to treat HER2-positive BC patients; however, the drug resistance remains a big challenge. Circular RNAs (circRNAs) are reported to be involved in drug resistance, but the role of circ_0001598 has never been studied in BC. First, we identified the expression of circ_0001598 by RT-qPCR in BC. The gain-of-function and loss-of-function studies were applied to study the functional roles of circ_0001598 and its target gene. We observed upregulation of circ_0001598 in BC tissues, especially in trastuzumab-resistant BC samples. We further identified that miR-1184 is a functional target of circ_0001598. Moreover, it was found that programmed death-ligand 1 (PD-L1) was a direct target of miR-1184. The oncogenic effects of circ_0001598 in promoting BC cell growth, trastuzumab-resistance, PD-L1 expression, and escaping of CD8 T cell killing were abolished after the restoration of miR-1184. In conclusion, we demonstrate that circ_0001598/miR-1184/PD-L1 signaling plays a crucial role in the regulation of BC progression and trastuzumab-resistance phonotypes, which suggests that circ_0001598 may be a molecular target to treat HER2-positive BC patients.

大约 25% 的乳腺癌 (BC) 患者是 HER2 阳性。曲妥珠单抗作为靶向治疗药物用于治疗 HER2 阳性 BC 患者；然而，耐药性仍然是一个巨大的挑战。据报道，环状 RNA（circRNAs）与耐药性有关，但 circ_0001598 的作用从未在 BC 进行过研究。首先，我们通过 RT-qPCR 在 BC 中鉴定了 circ_0001598 的表达。应用功能获得和功能丧失研究来研究circ_0001598及其靶基因的功能作用。我们观察到 BC 组织中 circ_0001598 的上调，尤其是在曲妥珠单抗耐药的 BC 样本中。我们进一步确定 miR-1184 是 circ_0001598 的功能靶点。此外，发现程序性死亡配体 1 (PD-L1) 是 miR-1184 的直接靶标。在 miR-1184 恢复后，circ_0001598 在促进 BC 细胞生长、曲妥珠单抗抗性、PD-L1 表达和逃避 CD8 T 细胞杀伤方面的致癌作用被取消。总之，我们证明 circ_0001598/miR-1184/PD-L1 信号在调节 BC 进展和曲妥珠单抗耐药表型中起关键作用，这表明 circ_0001598 可能是治疗 HER2 阳性 BC 患者的分子靶点。