Integrating molecular pathway with genome-wide association data for causality identification in breast cancer

TL;DR

This study finds a causal link between pyruvate metabolism and breast cancer, identifying key genes and potential drugs for targeted treatment.

Contribution

The study establishes a causal relationship between pyruvate metabolism and breast cancer using Mendelian randomization and identifies key metabolic genes.

Findings

Pyruvate metabolism is causally linked to breast cancer risk.

Genes ADH1B, ACSS2, ACACB, ADH1A, ALDH2, and ADH1C play important roles in breast cancer development.

Potential targeted drugs and a ceRNA regulatory network were identified for breast cancer treatment.

Abstract

The study purpose was to explore the causal association between pyruvate metabolism and breast cancer (BC), as well as the molecular role of key metabolic genes, by using bioinformatics and Mendelian randomization (MR) analysis.

We retrieved and examined diverse datasets from the GEO database to ascertain differentially acting genes (DAGs) in BC via differential expression analysis. Following this, we performed functional and pathway enrichment analyses to ascertain noteworthy molecular functions and metabolic pathways in BC. Employing MR analysis, we established a causal association between pyruvate metabolism and the susceptibility to BC. Additionally, utilizing the DGIdb database, we identified potential targeted medications that act on genes implicated in the pyruvate metabolic pathway and formulated a competing endogenous RNA (ceRNA) regulatory network in BC.

We collected the datasets GSE54002, GSE70947, and GSE22820, and identified a total of 1127 DEGs between the BC and NC groups. GO and KEGG enrichment analysis showed that the molecular functions of these DEGs mainly included mitotic nuclear division, extracellular matrix, signaling receptor activator activity, etc. Metabolic pathways were mainly concentrated in PI3K−Akt signaling pathway, Cytokine−cytokine receptor binding and Pyruvate, Tyrosine, Propanoate and Phenylalanine metabolism, etc. In addition, MR analysis demonstrated a causal relationship between pyruvate metabolism and BC risk. Finally, we constructed a regulatory network between pathway genes (ADH1B, ACSS2, ACACB, ADH1A, ALDH2, and ADH1C) and targeted drugs, as well as a ceRNA (lncRNA-miRNA-mRNA) regulatory network for BC, further revealing their interactions.

Our research revealed a causal association between pyruvate metabolism and BC risk, found that ADH1B, ACSS2, ACACB, ADH1A, ALDH2, and ADH1C takes place an important part in the development of BC in the molecular mechanisms related to pyruvate metabolism, and identified some potential targeted small molecule drugs.

The online version contains supplementary material available at 10.1007/s12672-024-01125-7.

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