通过综合组学分析和实验验证探索乳腺癌的新型治疗靶点。

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

作者信息

Chai Shengjun, Cui Jiayong, Sun Yinuo, Wang Xiaowu, Cai Chunmei

机构信息

Research Center for High Altitude Medicine, Qinghai University Medical College, Xining 810008, China.

Key Laboratory of the Ministry of High Altitude Medicine, Qinghai University Medical College, Xining 810008, China.

出版信息

Biology (Basel). 2025 Apr 11;14(4):405. doi: 10.3390/biology14040405.

DOI:10.3390/biology14040405

PMID:40282270

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12025194/

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.

摘要

背景

乳腺癌是全球女性癌症相关死亡的主要原因。解读乳腺癌的分子机制对于开发靶向治疗方法至关重要。

方法

本研究分析了基因表达综合数据库（GEO）中的基因表达谱，以鉴定乳腺癌中差异表达的基因（DEGs）。然后利用公开可用的eQTL数据库进行孟德尔随机化（MR）分析，以评估这些DEGs与乳腺癌之间的潜在因果关系。进一步进行富集分析以探索其功能意义。此外，使用癌症基因组图谱（TCGA）数据库对共表达基因进行外部验证。对选定的靶基因进行体外功能测定和药物敏感性分析，以验证它们在乳腺癌发病机制和治疗中的作用。

结果

在乳腺癌中总共鉴定出1052个上调基因和1380个下调基因。此外，MR分析揭示了12个可能导致乳腺癌发病机制的显著共表达基因。这些基因主要通过调节微小RNA功能和AMPK信号通路，在脂质代谢和免疫反应中富集。通过TCGA数据库验证证实了这些基因在乳腺癌组织中的差异表达。引人注目的是，对报道较少的基因DNASE2和ATOH8的功能测定表明，它们通过调节癌细胞的增殖、迁移和侵袭参与乳腺癌发病机制。值得注意的是，几种常用于乳腺癌治疗的临床药物，如5-氟尿嘧啶，对DNASE2和ATOH8的表达表现出显著增加的敏感性。