• Breast cancer brain metastasis (BCBM): microRNA-Gene interaction analysis
  • Hossein Noorollahi,1,* Maryam Moradi,2 Mohammad Reza Rahimpour,3 Naval Hamidi,4
    1. Islamic Azad University, Branch of Parand Tehran, Iran
    2. Islamic Azad University, Branch of Parand Tehran, Iran
    3. Islamic Azad University, Branch of Parand Tehran, Iran
    4. Islamic Azad University, Branch of Parand Tehran, Iran


  • Introduction: Breast cancer brain metastasis (BCBM) is a significant cause of brain metastases, particularly in patients with stage IV breast cancer. The incidence of brain metastases has been on the rise, with HER2-positive or triple-negative cancers associated with a higher risk. The understanding of the molecular mechanisms behind BCBM is still evolving, but specific gene mutations and expressional profiles in tumor cells have been identified. Treatment options for brain metastases include surgery, radiation therapy, and systemic therapy. MicroRNAs (miRNAs) play a crucial role in regulating cellular activities and are potential biomarkers for disease diagnosis and prognosis. Li et al. conducted a study analyzing mRNA and miRNA profiles in breast cancer specimens from patients with and without brain metastasis. The aim was to identify miRNAs associated with the pathways underlying BCBM. The study discovered several miRNAs linked to these pathways and further investigated their downstream molecular mechanisms through target genes. In this study, we first focused on identifying the most relevant microRNAs and their targets in breast cancer brain metastasis, and then investigated the downstream molecular mechanism using target genes.
  • Methods: In is study, the matrix data GSE100534 related to metastatic brain tissue derived from breast cancer with 35 samples downloaded from GEO database and were used to perform gene expression analysis by GEO2R. The level of p = 0.05 was used as the criterion for determining statistical significance and the threshold of |2| for Log 2 fold change was employed to identify differentially expressed genes (DEGs). MicroRNAs were predicted using the miRWalk database. Then, potential targets of the microRNAs were identified through the TargetScan, miRDB, and miRTarBase databases. The DAVID database was utilized to investigate the downstream regulatory pathways in KEGG. Target genes, were imported into Metascape for gene ontology and enrichment analysis. We also utilized Cytoscape software to conduct further analysis, using MCODE and CytoHubba plugins.
  • Results: 91 up-regulated genes and 25 down-regulated genes related to metastatic brain tissue derived from breast cancer were identified. For the up-regulated and down-regulated genes, 11 and 3 microRNAs were predicted respectively. The study found that hsa-miR-206, hsa-miR-7-5p, and hsa-miR-34a-5p microRNAs regulate down-regulated differentially expressed genes (DEGs). These microRNAs are enriched in the positive regulation of the miRNA transcription pathway. MCODE analysis identified a cluster of down-regulated target genes, including STX6, TFRC, and GJA1. Centrality analysis revealed that PDGFRA, CDK6, PIK3R3, MTMR9, TFRC, GJA1, KIF16B, ANKS1A, EGFR, and STX6 were the top hub genes based on the degree parameter. Dysregulation of GJA1 (Wu & Wang, 2019) and PDGFRA (Farooqi & Siddik, 2015) genes has been associated with various cancers, including breast cancer. The study suggests that the down-regulation of genes STX6, TFRC, and GJA1 through the activation of the positive regulation of miRNA transcription pathway leads to the activation of microRNAs, which promote brain metastasis in breast cancer. The study identified several microRNAs that are involved in the regulation of up-regulated differentially expressed genes (DEGs). These microRNAs are enriched in positive regulation of the miRNA metabolic process. Through MCODE analysis, a cluster of target genes was identified, including CCNT2, CCND1, E2F2, CCNY, CCND2, CCNE2, CCNJ, CDKN1A, and CDC25A. Centrality analysis highlighted hub genes such as CCND1, CSNK2A1, POLR2D, CCND2, CDKN1A, SMAD4, MYCN, and CBX5. The study suggests that the up-regulation of these genes leads to the activation of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-5p, hsa-let-7e-5p, hsa-miR-98-5p, hsa-miR-23a-3p, hsa-miR-485-3p, hsa-miR-485-5p, hsa-miR-449a, and hsa-miR-449b-5p microRNAs, which in turn promote brain metastasis in breast cancer.
  • Conclusion: MicroRNA plays a crucial role in regulating gene expression and controlling cellular processes. Understanding the pathways affected by microRNA target genes is important for understanding their function and their association with diseases. In the case of brain metastasis, inhibiting the growth and invasion of primary tumors, such as breast cancer, could be a potential treatment approach. MicroRNAs and their targets can be used to suppress these pathways. Identifying target genes regulated by microRNAs can provide valuable insights into disease mechanisms and aid in the development of effective therapies.
  • Keywords: Breast cancer brain metastasis, microRNA, miR-Gene interaction analysis