INTRODUCTION: Breast cancer is the most common cancer and the leading cause of cancer-related death in women. Differential gene expression can help identify genes involved in carcinogenesis or serve as biomarkers. METHODS: This study provides a comprehensive evaluation of the gene expression focusing on apoptosis-related genes, in invasive breast carcinoma of no specific type compared with benign tissue. The gene expression of nine candidate genes identified as potential targets of certain microRNAs suggested as biomarkers and known for their role in apoptosis, and two additional apoptosis-related genes identified in the screening was evaluated using qPCR together with external datasets. RESULTS: Screening of 92 apoptosis-related genes identified several dysregulated genes including downregulated BCL2L2 and upregulated BIRC5 genes, which were further confirmed as tumor suppressor and as an oncogene, respectively. Among the miRNA-related genes, HMGA2 and RAB22A were overexpressed, while ATF2, PPM1L, VPS4A, ZEB1, and ZFP36L1 were underexpressed. The BIRC5/BCL2L2 gene signature provided AUC of 0.975, sensitivity of 93.10% and specificity of 96.43%. Increased BIRC5 expression was associated with higher tumor grades and Ki-67-positive samples while decreased levels of BCL2L2 were associated with Ki-67-positive samples. Luminal A and B samples were distinguished by the differential expression of these two genes. The high expression of HMGA2 and BIRC5 genes was observed as a negative prognostic factor for both overall survival (OS) and progression-free survival (PFS) with a favorable OS difference of ~ 1 year for HMGA2 and 1.2 years for BIRC5 in the case of their low expression. External validation identified ZEB1 as a positive and BIRC5 as a negative prognostic factor for both overall and disease-free survival. CONCLUSION: The results highlighted genes with possible roles in apoptosis and acting in breast carcinogenesis. In particular, BIRC5 was shown as important oncogene and ZEB1 as a tumor suppressor in invasive breast cancer. Further studies are warranted to evaluate the potential of the investigated genes as biomarkers or therapeutic targets, with possible implications for breast cancer diagnosis and treatment.

3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Obstetrics and Gynecology Masaryk University University Hospital Brno Obilní trh 11 Brno 60200 Czech Republic

Department of Pathology Faculty of Medicine Masaryk University University Hospital Brno Obilní trh 11 Brno 60200 Czech Republic

Institute for Postgraduate Medical Education IPVZ Prague Czech Republic

Institute for the Care of Mother and Child Podolské Nábřeží 157 36 Prague Podolí 14700 Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University General University Hospital Prague Albertov 4 Prague 12800 Czech Republic

Institute of Pharmacology 1st Faculty of Medicine Charles University General University Hospital Prague Albertov 4 Prague 12800 Czech Republic

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