Investigating tumor suppressor function and regulatory control of NISCH in breast cancer

Purpose: This study aimed to characterize the role of Nischarin (NISCH) in breast cancer by examining its expression patterns in relation to clinical outcomes and exploring potential regulatory mechanisms-specifically promoter methylation and copy number alterations-that may underlie its dysregulation. Methods: Data were acquired for NISCH from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) via UCSC Xena and cBioPortal, including expression levels of NISCH and several DNA methyltransferases (DNMTs), promoter methylation beta values, copy-number values, demographic variables, and clinical data. All retrospective analyses were performed using GraphPad Prism. Results: High expression of NISCH was significantly associated with improved overall survival in breast cancer, as well as longer distant metastasis-free survival and relapse-free survival. When comparing demographics, a lower expression of NISCH was observed in patients diagnosed at younger ages, within the Basal PAM-50 subtype, and among the Asian race. Several CpG islands proximal to the promoter region showed both a negative correlation with NISCH expression and elevated methylation in tumor samples. Co-expression studies revealed inverse correlations between three DNMTs and NISCH, indicating possible involvement in the silencing of the gene. Furthermore, shallow deletions at the NISCH locus correlated with reduced mRNA expression and were linked to poorer survival outcomes. Conclusions: Together these findings support NISCH's profile as a tumor suppressor in breast cancer, with high mRNA expression consistently linked to better survival outcomes across multiple clinical metrics. Moreover, identifying lower NISCH expression in biologically aggressive subsets of breast cancer-the Basal PAM-50 subtype and younger age at diagnosis-enhances NISCH as a putative marker for poor prognosis. Both promoter methylation and shallow deletions reduced expression of NISCH, indicating that the locus may be regulated through several genomic and epigenetic mechanisms. Inverse expression patterns between NISCH and three DNMTs across similar demographic subsets provides additional evidence that promoter-methylation may drive the silencing process. Collectively, these findings strengthen the rationale for future functional studies to investigate the mechanisms controlling NISCH expression, and to evaluate its potential as a biomarker or therapeutic target in breast cancer.