Abstract
Brain metastases represent a major cause of mortality among patients with breast cancer, and few effective targeted treatment options are currently available. Development of new biomarkers and therapeutic targets for breast cancer brain metastases (BCBM) is therefore urgently needed. In this study, we compared the gene expression profiles of the brain metastatic cell line MDA-MB-231-BR (231-BR) and its parental MDA-MB-231, and identified a total of 84 genes in the primary screening through a series of bioinformatic analyses, including construction of protein-protein interaction (PPI) networks by STRING database, identification of hub genes by applying of MCODE and Cytohubba algorithms, identification of leading-edge subsets of Gene Set Enrichment Analysis (GSEA), and identification of most up-regulated genes. Eight genes were identified as candidate genes due to their elevated expression in brain metastatic 231-BR cells and prognostic values in patients with BCBM. Then we knocked down the eight individual candidate genes in 231-BR cells and evaluated their impact on cell migration through a wound-healing assay, and four of them (KRT19, FKBP10, GSK3B and SPANXB1) were finally identified as key genes. Furthermore, the expression of individual key genes showed a correlation with the infiltration of major immune cells in the brain tumor microenvironment (TME) as analyzed by Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA), suggesting possible roles of them in regulation of the tumor immune response in TME. Therefore, the present work may provide new potential biomarkers for BCBM. Additionally, using GSEA, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Enrichment Analysis, we determined the top enriched cellular functions or pathways in 231-BR cells, which may help better understand the biology governing the development and progression of BCBM.
Highlights
Brain metastases are the most common malignant brain tumors and are the frontier for the management of metastatic cancer patients [1, 2]
In the search for novel genes related to the pathogenesis of breast cancer brain metastasis, differentially expressed genes (DEGs) between 231-BR and MDA-MB-231 cells were screened and identified by RNA sequencing
As microglia (MG), monocyte-derived macrophages (MDMs), neutrophils, and CD8+ and CD4+ T cells have been confirmed to be the major immune cell determinants of the brain tumor microenvironment (TME) landscape [47], we investigated the association between the key genes and the above immune cells based on immune biomarkers
Summary
Brain metastases are the most common malignant brain tumors and are the frontier for the management of metastatic cancer patients [1, 2]. Even small lesions can cause neurological disability, and the median survival of patients with brain metastases is less than 1 year [3,4,5]. The cumulative incidence of identified brain metastases among patients with breast cancer (all stages at diagnosis) was not high (about 5.1%); it varies by subtype. Patients with HER2-positive (34% to 55%) or triple-negative (22% to 46%) subtypes experience significantly higher brain metastasis occurrence than patients with other subtypes [8,9,10]. Prognosis after brain metastases is subtype-dependent, and triple-negative breast cancer (TNBC) patients showed the shortest survival time after brain metastasis than other subtypes, which is only 4.9 months [9, 11]
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