Cathepsins E, O, and S: Novel Biomarkers and Therapeutic Targets in Breast Carcinoma.

[AIM] This study aimed to investigate the causal associations between nine cathepsins (B, E, F, G, H, L2, O, S, Z) and breast carcinogenesis using Mendelian Randomization (MR) analysis, thereby addressing the current lack of systematic causal evidence beyond observational studies.

[METHODS] Genetic instruments for circulating cathepsin levels were obtained from the INTERVAL study, and summary statistics for breast cancer were derived from the TRICL consortium. Univariate MR with Inverse Variance Weighting (IVW) served as the primary analysis, supplemented by assessments of heterogeneity, pleiotropy, and outliers. Multivariable MR was performed to confirm independent associations, and reverse MR was used to explore potential feedback from breast cancer to cathepsin expression.

[RESULTS] Higher genetically predicted cathepsin E was causally associated with an increased risk of breast cancer, whereas cathepsins O and S were protective. No significant associations were observed for the other six cathepsins. Multivariable MR confirmed these associations as independent of one another. Reverse MR suggested that breast cancer liability downregulates cathepsin H but does not influence cathepsins E, O, or S.

[CONCLUSION] This is the first MR study to provide causal evidence implicating cathepsin E as a risk factor and cathepsins O and S as protective factors in breast cancer. The findings highlight the novelty of identifying specific cathepsins with opposing effects, nominating cathepsin E as a candidate serum biomarker and cathepsins O and S as potential therapeutic targets. These results warrant validation in diverse, multi-ethnic cohorts and longitudinal studies.