Unraveling the causal relationship and potential mechanisms between osteoarthritis and breast cancer: insights from mendelian randomization and bioinformatics analysis.

Objective: To investigate the effect of osteoarthritis (OA) on the development of breast cancer (BC), and reveal the potential mechanisms underlying the association between them.

Methods: A two-step, multivariable Mendelian Randomization (MR) analysis was performed, using statistics from genome-wide association studies (GWAS), to determine the effect of OA on BC and explore the role of major depressive disorder (MDD) in mediating it. Furthermore, transcriptomic analysis based on the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to establish a prognostic model and explore the underlying mechanisms. Additionally, BC cells and nude mice were used to verify the role of RTN4 in BC.

Results: The two-sample MR analysis implied a causal relationship between OA and BC at the genetic level, and the mediating MR analysis identified that MDD may play a potential role in mediating it, accounting for approximately 12.20%. Then, we constructed a prognostic model (OA-score) with six genes screened out from datasets and selected RTN4 as the representative gene for validation study. It was demonstrated that high OA-score was an independent risk factor for breast cancer, and patients with low OA-score were more likely to have better OS, higher infiltration level of DC and CD 4 + T cells, and higher expression of some immune checkpoints. Moreover, the knockdown of RTN4 inhibited breast cancer cell proliferation, migration and invasion.

Conclusion: Our study identified the causal influence of OA on BC mediated by MDD at the genetic level. OA-Score may potentially serve as a new prognostic biomarker for OA related BC patients.