Genetic and Molecular Mechanisms Linking Breast Cancer to Meningioma Risk: Roles of EXO1, BRCA2, and ESR1

Epidemiological evidence suggests increased meningioma risk in breast cancer patients, but causal relationships and underlying mechanisms remain unclear.

We performed two-sample Mendelian Randomization (MR) using 119 genome-wide significant SNPs to assess the causal effect of breast cancer on meningioma risk. Weighted Gene Co-Expression Network Analysis (WGCNA) identified shared gene modules, intersected with MR-nearby genes to pinpoint hub genes. Functional validation was conducted via in vitro assays in breast cancer (MCF7, MDA-MB-231) and meningioma (CH157-MN) cell lines. Candidate drug prediction was performed using Enrichr.

MR analysis demonstrated a significant causal effect of breast cancer on meningioma risk (OR=1.22, 95% CI:1.09-1.37, p<0.01) without evidence of pleiotropy or reverse causation. WGCNA identified the MEblue module as highly correlated with both cancers; intersection with MR genes revealed EXO1, BRCA2, and ESR1 as key hub genes. These genes were upregulated in tumors, showing robust diagnostic performance (AUC>0.71). Knockdown experiments increased DNA damage and apoptosis, while ESR1 knockdown inhibited proliferation and invasion. Co-culture assays upregulated hub genes and inflammatory cytokines (IL-6, TNF-α). Azacitidine significantly downregulated these genes in MCF7 cells.

Our integrative approach confirms breast cancer as a potential causal risk factor for meningioma mediated by EXO1-, BRCA2-, and ESR1-driven DNA repair and estrogen signaling pathways. Functional assays highlight their roles in tumor progression and microenvironmental inflammation via NF-κB signaling. Clinically, these genes may serve as biomarkers for early meningioma screening and as therapeutic targets. Azacitidine emerges as a promising candidate for precision intervention. Limitations include phenotype heterogeneity and lack of in vivo validation, warranting further study.

This study provides genetic and functional evidence linking breast cancer to meningioma risk through DNA repair and hormonal pathways, supporting early risk assessment and targeted therapies to improve patient outcomes.