Screening and Identification of Novel Potential Biomarkers for Breast Cancer Brain Metastases

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.

Melatonin Alleviates Oxidative Stress Induced by H2O2 in Porcine Trophectoderm Cells

“…Then, the protein–protein interaction network (PPIs) information of these DEGs was predicted by the STRING database (version 11.5) [ 34 ]. After mapping the DEGs into this database, and a combined score ≥ 0.4 was exported [ 35 ]. Then, the PPIs of these DEGs were visualized in Cytoscape, and the hub genes among the PPI network were identified and ranked using the CytoHubba plugin and the maximal clique centrality (MCC) method of Cytoscape software (Version 3.8.2; The Cytoscape Consortium, New York, NY, USA).…”

Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells

“…Breast cancer is the most commonly diagnosed cancer in women worldwide ( Arnold et al, 2022 ), with an estimated 10%–35% of breast cancer patients developing metastasis to the brain ( Tsukada et al, 1983 ; Patanaphan et al, 1988 ; Willett et al, 2015 ). Breast-cancer brain metastases (BCBM) currently represent an incurable event ( Wang et al, 2021 ), with over 80% of patients succumbing to end-stage disease within a year of diagnosis ( Dawood et al, 2012 ; Arnold et al, 2022 ). Limited therapeutic interventions, including surgical resection, whole brain radiation, and chemotherapy, are often ineffective and yield detrimental effects on healthy brain tissue, thereby profoundly diminishing the quality of life of affected patients ( Leone and Leone, 2015 ; Wang et al, 2021 ; Watase et al, 2021 ).…”

Discovery of novel brain permeable human ACSS2 inhibitors for blocking breast cancer brain metastatic growth

“…Breast-cancer brain metastases (BCBM) currently represent an incurable event [5], with over 80% of patients losing their lives within a year of diagnosis [1, 6]. Limited therapeutic interventions, including surgical resection, whole brain radiation, and chemotherapy, are often ineffective and yield detrimental effects on healthy brain tissue, thereby profoundly diminishing the quality of life of affected patients [5, 7, 8]. Thus, there is an urgent need to identify small molecules that can block tumor growth in the brain.…”

“…Breast cancer is the most commonly diagnosed cancer in women worldwide [1], with an estimated 10-35% of breast cancer patients developing metastasis to the brain [2][3][4]. Breast-cancer brain metastases (BCBM) currently represent an incurable event [5], with over 80% of patients losing their lives within a year of diagnosis [1,6]. Limited therapeutic interventions, including surgical resection, whole brain radiation, and chemotherapy, are often ineffective and yield detrimental effects on healthy brain tissue, thereby profoundly diminishing the quality of life of affected patients [5,7,8].…”