Dahi Farzaneh, Shahbazi Shirin, Geranpayeh Loabat
Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Department of Surgery, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Bioimpacts. 2025 Aug 9;15:30792. doi: 10.34172/bi.30792. eCollection 2025.
Mitochondrial DNA (mtDNA) copy number variations have been reported in multiple human cancers. Previous studies indicate that mitochondrial retrograde signaling regulates , which plays a key role in tumorigenesis, including regulating apoptosis antagonizing transcription factor (). This study investigates the expression of and in relation to mtDNA copy number in invasive ductal carcinoma (IDC) of the breast.
Paired primary tumors and adjacent non-tumor tissues were analyzed to assess changes in and expression using fold-change analysis. The mtDNA copy number was quantified using as the mitochondrial gene and as the nuclear control gene. To validate the findings, publicly available data from The Cancer Genome Atlas (TCGA) were also analyzed.
A significant reduction in tumor expression was observed (fold change=0.139), with a strong correlation between and expression. A significant Z-score difference was also detected between and mtDNA copy number. was predominantly expressed in grade I tumors but significantly downregulated in higher-grade tumors, whereas expression increased with tumor grade. In silico analysis of TCGA data confirmed elevated expression, with notable variations across breast cancer subtypes.
We observed reduced expression of and mtDNA copy number in breast tumors, along with variations in levels across subtypes. The decrease in could be associated with lower mtDNA copy numbers and impaired retrograde signaling, impacting 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.
线粒体DNA（mtDNA）拷贝数变异已在多种人类癌症中被报道。先前的研究表明，线粒体逆行信号传导起调节作用，这在肿瘤发生中起关键作用，包括调节细胞凋亡拮抗转录因子（）。本研究调查了乳腺癌浸润性导管癌（IDC）中与mtDNA拷贝数相关的和的表达情况。
分析配对的原发性肿瘤和相邻的非肿瘤组织，使用倍数变化分析来评估和表达的变化。使用作为线粒体基因和作为核对照基因来定量mtDNA拷贝数。为了验证研究结果，还分析了来自癌症基因组图谱（TCGA）的公开可用数据。
观察到肿瘤表达显著降低（倍数变化=0.139），和表达之间存在强相关性。在和mtDNA拷贝数之间也检测到显著的Z分数差异。主要在I级肿瘤中表达，但在高级别肿瘤中显著下调，而表达随肿瘤分级增加。对TCGA数据的计算机分析证实表达升高，在乳腺癌亚型中存在显著差异。
我们观察到乳腺肿瘤中表达和mtDNA拷贝数降低，以及各亚型间水平存在差异。的降低可能与较低的mtDNA拷贝数和受损的逆行信号传导有关，影响表达和功能。我们的研究结果强调了靶向mtDNA/miR-663/AATF轴的治疗前景，这可能会推动乳腺癌治疗的进展。
