Abstract
Female breast cancer (BCa) is the most commonly occurring cancer worldwide. The tumor microenvironment (TME) plays an essential role in tumor invasion, angiogenesis, unlimited proliferation, and even immune escape, but we know little about the TME of BCa. In this study, we aimed to find a TME-related biomarker for BCa, especially for invasive breast carcinoma (BRCA), that could predict prognosis and immunotherapy efficacy. Based on RNA-seq transcriptome data and the clinical characteristics of 1222 samples (113 normal and 1109 tumor samples) from The Cancer Genome Atlas (TCGA) database, we used the ESTIMATE algorithm to calculate the ImmuneScore and StromalScore and then identified differentially expressed genes (DEGs) between the high and low ImmuneScore groups and the high and low StromalScore groups. Thereafter, a protein–protein interaction (PPI) network analysis and univariate Cox regression analyses of overall survival were used to identify potential key genes. Five candidate genes were identified, comprising CD2, CCL19, CD52, CD3E, and ITK. Thereafter, we focused on CD2, analyzing CD2 expression and its association with survival. CD2 expression was associated with tumor size (T stage) to some extent, but not with overall TNM stage, lymph node status (N stage), or distant metastasis (M stage). High CD2 expression was associated with longer survival. METABRIC data were used to validate the survival result (n = 276). Gene set enrichment analysis (GSEA) showed that the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that were significantly associated with high CD2 expression were mainly immune-related pathways. Furthermore, CD2 expression was correlated with 16 types of tumor-infiltrating immune cells (TICs). Hence, CD2 might be a novel biomarker in terms of molecular typing, and it may serve as a complementary approach to TNM staging to improve clinical outcome prediction for BCa patients.
Highlights
According to the latest global cancer data published by the International Agency for Research on Cancer (IARC), female breast cancer (BCa) is the most commonly occurring cancer worldwide [1]
Based on the transcriptome data and clinical characteristics related to 1222 samples (113 normal and 1,109 tumor samples) from the The Cancer Genome Atlas (TCGA) database, ImmuneScore and StromalScore were calculated by ESTIMATE algorithms to assess the immune and stromal components, and CIBERSORT algorithms were used to estimate the proportions of tumor-infiltrating immune cells (TICs)
CD2, CCL19, CD52, CD3E, and ITK were identified based on the intersection of the hub genes in the protein–protein interaction (PPI) network and the 59 significant genes in the univariate Cox regression analyses
Summary
According to the latest global cancer data published by the International Agency for Research on Cancer (IARC), female breast cancer (BCa) is the most commonly occurring cancer worldwide [1]. The American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) classification can be used to estimate the tumor burden and prognosis of BCa patients, clinical outcomes do not always relate to the tumor histological stage [4,5,6]. Research has indicated that using the TME-related ImmuneScore and the proportions of tumor-infiltrating immune cells (TICs) in the tumor microenvironment (TME) may improve the prediction of several cancer prognosis [7, 8]. The BCa TME is composed of heterogeneous immune and stromal cells, which play vital roles in regulating both BCa initiation and progression and the clinical responses to therapies [12]. In colorectal cancer, the TME-related ImmuneScore has been shown to be an effective indicator of cancer recurrence, metastasis, and prognosis [7]. Little is known about the BCa TME, but there is much interest in identifying novel prognostic and therapeutic biomarkers across the distinct pathomolecular subtypes of BCa
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