Mtdna Copy Number/Mir663/Aatf Axis in Invasive Ductal Carcinoma of the Breast Publisher



F Dahi FARZANEH ; S Shahbazi SHIRIN ; L Geranpayeh LOBAT
Source: BioImpacts Published:2025

Abstract

Introduction: Mitochondrial DNA (mtDNA) copy number variations have been reported in multiple human cancers. Previous studies indicate that mitochondrial retrograde signaling regulates miR663, which plays a key role in tumorigenesis, including regulating apoptosis antagonizing transcription factor (AATF). This study investigates the expression of miR663 and AATF in relation to mtDNA copy number in invasive ductal carcinoma (IDC) of the breast. Methods: Paired primary tumors and adjacent non-tumor tissues were analyzed to assess changes in miR663 and AATF expression using fold-change analysis. The mtDNA copy number was quantified using COX1 as the mitochondrial gene and COX4 as the nuclear control gene. To validate the findings, publicly available data from The Cancer Genome Atlas (TCGA) were also analyzed. Results: A significant reduction in tumor miR663 expression was observed (fold change = 0.139), with a strong correlation between miR663 and AATF expression. A significant Z-score difference was also detected between miR663 and mtDNA copy number. miR663 was predominantly expressed in grade I tumors but significantly downregulated in higher-grade tumors, whereas AATF expression increased with tumor grade. In silico analysis of TCGA data confirmed elevated AATF expression, with notable variations across breast cancer subtypes. Conclusion: We observed reduced expression of miR663 and mtDNA copy number in breast tumors, along with variations in AATF levels across subtypes. The decrease in miR663 could be associated with lower mtDNA copy numbers and impaired retrograde signaling, impacting AATF expression and function. Our findings underscore the therapeutic promise of targeting the mtDNA/miR-663/AATF axis, which could lead to advancements in breast cancer treatment. © 2025 Elsevier B.V., All rights reserved.