Exploring Novel Therapeutic Targets in Breast Cancer via Comprehensive Omics Profiling and Experimental Verification

Abstract

Background: Breast cancer is the leading cause of cancer-related deaths among women worldwide. Deciphering the molecular mechanisms of breast cancer is crucial for developing targeted therapeutic approaches. Methods: This study analyzed gene expression profiles from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) in breast cancer. Mendelian randomization (MR) analysis was then employed using publicly available eQTL databases to evaluate potential causal relationships between these DEGs and breast cancer. Enrichment analyses were further conducted to explore their functional significance. Furthermore, external validation of co-expressed genes was conducted using The Cancer Genome Atlas (TCGA) database. In vitro functional assays and drug sensitivity analyses were performed on selected target genes to validate their roles in breast cancer pathogenesis and treatment. Results: A total of 1052 upregulated and 1380 downregulated genes were identified in breast cancer. Additionally, MR analysis revealed 12 significant co-expressed genes potentially contributing to breast cancer pathogenesis. These genes were primarily enriched in lipid metabolism and immune responses via regulating microRNA functions and AMPK signaling. Validation through the TCGA database confirmed differential expression of these genes in breast cancer tissues. Strikingly, functional assays of the less-reported genes DNASE2 and ATOH8 demonstrated their involvement in breast cancer pathogenesis through modulating proliferation, migration, and invasion of cancer cells. Notably, several commonly used clinical drugs for breast cancer management, such as 5-Fluorouracil, exhibited dramatically increased sensitivity to DNASE2 and ATOH8 expression. Conclusions: Our study provides novel insights into the molecular basis of breast cancer pathogenesis and identifies promising therapeutic strategies for this condition.

Keywords

• Mendelian randomization
• breast cancer
• ATOH8
• DNASE2
• experimental validation