Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham, NG7 2RD, UK.
Department of Laboratory Medical Science, Faculty of Applied Medical Science, Shaqra University, Shaqra, Saudi Arabia.
Breast Cancer Res Treat. 2021 Jan;185(2):293-305. doi: 10.1007/s10549-020-05955-1. Epub 2020 Oct 19.
Lymphovascular invasion (LVI) is a prognostic factor in early-stage invasive breast cancer (BC). Through bioinformatics, data analyses of multiple BC cohorts revealed the positive association between interferon-stimulated gene 15 (ISG15) LVI status. Thus, we explored the prognostic significance of ISG15 in BC.
The prognostic significance of ISG15 mRNA was assessed in METABRIC (n = 1980), TCGA (n = 854) and Kaplan-Meier Plotter (n = 3951). ISG15 protein was evaluated using immunohistochemistry (n = 859) in early-stage invasive BC patients with long-term follow-up. The associations between ISG15 expression and clinicopathological features, expression of immune cell markers and patient outcome data were evaluated.
High mRNA and protein ISG15 expression were associated with LVI, higher histological grade, larger tumour size, hormonal receptor negativity, HER2 positivity, p53 and Ki67. High ISG15 protein expression was associated with HER2-enriched BC subtypes and immune markers (CD8, FOXP3 and CD68). High ISG15 mRNA and ISG15 expressions were associated with poor patient outcome. Cox proportional multivariate analysis revealed that the elevated ISG15 expression was an independent prognostic factor of shorter BC-specific survival.
This study provides evidence for the role of ISG15 in LVI development and BC prognosis. Further functional studies in BC are warranted to evaluate the therapeutic potential of ISG15.
淋巴血管侵犯（LVI）是早期浸润性乳腺癌（BC）的预后因素。通过生物信息学，对多个 BC 队列的数据进行分析，揭示了干扰素刺激基因 15（ISG15）LVI 状态与阳性之间的关联。因此，我们探讨了 ISG15 在 BC 中的预后意义。
在 METABRIC（n=1980）、TCGA（n=854）和 Kaplan-Meier Plotter（n=3951）中评估了 ISG15 mRNA 的预后意义。使用免疫组织化学（n=859）评估了早期浸润性 BC 患者的 ISG15 蛋白，这些患者具有长期随访。评估了 ISG15 表达与临床病理特征、免疫细胞标志物表达和患者预后数据之间的关系。
高 mRNA 和蛋白 ISG15 表达与 LVI、较高的组织学分级、较大的肿瘤大小、激素受体阴性、HER2 阳性、p53 和 Ki67 相关。高 ISG15 蛋白表达与 HER2 富集的 BC 亚型和免疫标志物（CD8、FOXP3 和 CD68）相关。高 ISG15 mRNA 和 ISG15 表达与患者预后不良相关。Cox 比例风险多变量分析显示，升高的 ISG15 表达是 BC 特异性生存时间较短的独立预后因素。
本研究为 ISG15 在 LVI 发展和 BC 预后中的作用提供了证据。需要进一步在 BC 中进行功能研究，以评估 ISG15 的治疗潜力。
