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

## TL;DR

This study identifies new genes linked to breast cancer and shows how they affect cancer growth and drug response, offering potential new treatment targets.

## Contribution

The study identifies 12 causally linked genes, including DNASE2 and ATOH8, as novel therapeutic targets in breast cancer.

## Key findings

- DNASE2 promotes breast cancer cell proliferation, migration, and invasion.
- ATOH8 suppresses breast cancer cell proliferation, migration, and invasion.
- 5-Fluorouracil shows enhanced efficacy in patients with high DNASE2 or ATOH8 expression.

## Abstract

Breast cancer remains a leading cause of cancer-related deaths in women globally, with current therapies often limited by resistance and lack of broad applicability. This study aimed to identify novel molecular targets for breast cancer treatment by integrating multi-omics data and experimental validation. Using gene expression datasets from public databases, we identified 1052 upregulated and 1380 downregulated genes in breast cancer. Through Mendelian randomization analysis, 12 key genes were found to be causally linked to breast cancer pathogenesis, including DNASE2 and ATOH8, which were further validated in external datasets. Functional experiments revealed that ATOH8 suppresses breast cancer cell proliferation, migration, and invasion, while DNASE2 promotes these processes. Drug sensitivity analysis highlighted that drugs like 5-Fluorouracil show enhanced efficacy in patients with high DNASE2 or ATOH8 expression. These findings uncover new therapeutic targets and provide insights into personalized treatment strategies for breast cancer.

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.