School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK.
Biomedical Science Program, Faculty of Medicine Siriraj Hospital, University of Mahidol, Bangkok, Thailand.
Cancer Med. 2023 Jun;12(12):13225-13240. doi: 10.1002/cam4.6014. Epub 2023 May 18.
Triple-negative breast cancer (TNBC) patients have the poorest clinical outcomes compared to other molecular subtypes of breast cancer. IL6/JAK/STAT3 signalling is upregulated in breast cancer; however, there is limited evidence for its role in TNBC. This study aimed to assess the expression of IL6/JAK/STAT3 in TNBC as a prognostic biomarker.
Tissue microarrays consisting of breast cancer specimens from a retrospective cohort (n = 850) were stained for IL6R, JAK1, JAK2 and STAT3 via immunohistochemistry. Staining intensity was assessed by weighted histoscore and analysed for association with survival/clinical characteristics. In a subset of patients (n = 14) bulk transcriptional profiling was performed using TempO-Seq. Nanostring GeoMx® digital spatial profiling was utilised to establish the differential spatial gene expression in high STAT3 tumours.
In TNBC patients, high expression of stromal STAT3 was associated with reduced cancer-specific survival (HR = 2.202, 95% CI: 1.148-4.224, log rank p = 0.018). TNBC patients with high stromal STAT3 had reduced CD4 T-cell infiltrates within the tumour (p = 0.001) and higher tumour budding (p = 0.003). Gene set enrichment analysis (GSEA) of bulk RNA sequencing showed high stromal STAT3 tumours were characterised by enrichment of IFNγ, upregulation of KRAS signalling and inflammatory signalling Hallmark pathways. GeoMx™ spatial profiling showed high stromal STAT3 samples. Pan cytokeratin (panCK)-negative regions were enriched for CD27 (p < 0.001), CD3 (p < 0.05) and CD8 (p < 0.001). In panCK-positive regions, high stromal STAT3 regions had higher expression of VEGFA (p < 0.05).
High expression of IL6/JAK/STAT3 proteins was associated with poor prognosis and characterised by distinct underlying biology in TNBC.
与其他乳腺癌分子亚型相比，三阴性乳腺癌（TNBC）患者的临床预后最差。IL6/JAK/STAT3 信号在乳腺癌中上调；然而，其在 TNBC 中的作用证据有限。本研究旨在评估 IL6/JAK/STAT3 在 TNBC 中的表达作为一种预后生物标志物。
使用组织微阵列对回顾性队列（n=850）的乳腺癌标本进行 IL6R、JAK1、JAK2 和 STAT3 的免疫组织化学染色。通过加权组织评分评估染色强度，并分析其与生存/临床特征的关联。在部分患者（n=14）中，使用 TempO-Seq 进行批量转录谱分析。利用 Nanostring GeoMx®数字空间分析技术，确定高 STAT3 肿瘤中的差异空间基因表达。
在 TNBC 患者中，基质 STAT3 高表达与癌症特异性生存降低相关（HR=2.202，95%CI：1.148-4.224，对数秩检验 p=0.018）。高基质 STAT3 的 TNBC 患者肿瘤内 CD4 T 细胞浸润减少（p=0.001），肿瘤芽生增加（p=0.003）。批量 RNA 测序的基因集富集分析（GSEA）显示，高基质 STAT3 肿瘤的特征是 IFNγ 富集、KRAS 信号和炎症信号通路标志途径上调。GeoMx™空间分析显示高基质 STAT3 样本。panCK 阴性区域富含 CD27（p<0.001）、CD3（p<0.05）和 CD8（p<0.001）。在 panCK 阳性区域，高基质 STAT3 区域 VEGFA 表达更高（p<0.05）。
IL6/JAK/STAT3 蛋白的高表达与预后不良相关，并在 TNBC 中具有独特的潜在生物学特征。
