Data Sheet 2_Investigating the role of cathepsins in breast cancer progression: a Mendelian randomization study.pdf

BackgroundBreast cancer, a major threat to women’s health worldwide, has mechanisms of onset that remain unclear. Within the human lysosomal system, a class of enzymes known as cathepsins exhibit elevated expression levels in various malignant tumors, suggesting that they may play key roles in cancer progression.
MethodsThis study employed the two-sample Mendelian randomization (MR) approach to investigate the potential causal relationship between cathepsin levels and the risk of developing breast cancer. Furthermore, we conducted MR analysis using eQTL data to investigate how gene expression, mediated by cathepsins, affects the occurrence of different types of breast cancer and assessed the regulatory effects of cathepsins.
ResultsMR analysis revealed that increased levels of cathepsin E are associated with a greater risk of malignant breast tumors (IVW: p = 0.006, OR = 1.103, 95% CI = 1.028–1.184), and increased levels of cathepsin F are associated with an increased risk of in situ breast cancer (IVW: p = 0.031, OR = 1.190, 95% CI = 1.016–1.394). Additionally, cathepsin Z has a protective effect against in situ breast cancer (IVW: p = 0.017, OR = 0.846, 95% CI = 0.737-0.971). Cathepsin E can mediate the effects of APBB1IP, NT5C3B, and ZNF66 on HER2-negative breast cancer, as well as the effects of DHRS9, CDK12, and CD247 on HER2-positive breast cancer. Cathepsin F can mediate the effects of ANXA2R and ZNF605 on in situ breast cancer. Cathepsin Z can mediate the effects of PRX, CRY2, ADCY3, and PELATON on in situ breast cancer.
DiscussionThese findings highlight the dual roles of cathepsins as potential risk and protective factors for breast cancer, underscoring their potential in diagnostic and therapeutic strategies.

背景 乳腺癌是全球范围内威胁女性健康的重大公共卫生问题，其具体发病机制尚未完全阐明。在人类溶酶体系统中，组织蛋白酶（cathepsins）这一类酶在多种恶性肿瘤中呈现表达上调特征，提示其可能在肿瘤进展过程中发挥关键调控作用。
方法 本研究采用两样本孟德尔随机化（two-sample Mendelian randomization，MR）方法，探究组织蛋白酶水平与乳腺癌发病风险之间的潜在因果关联。此外，本研究借助表达数量性状位点（expression quantitative trait locus，eQTL）数据开展孟德尔随机化分析，以明确组织蛋白酶介导的基因表达如何影响不同亚型乳腺癌的发生，并评估组织蛋白酶的调控效应。
结果 孟德尔随机化分析结果显示，组织蛋白酶E（cathepsin E）水平升高与恶性乳腺肿瘤发病风险增加显著相关（逆方差加权法（inverse variance weighting，IVW）：p=0.006，比值比（odds ratio，OR）=1.103，95%置信区间（confidence interval，CI）=1.028~1.184）；组织蛋白酶F（cathepsin F）水平升高与原位乳腺癌发病风险升高呈显著正相关（逆方差加权法：p=0.031，OR=1.190，95%CI=1.016~1.394）。此外，组织蛋白酶Z（cathepsin Z）对原位乳腺癌具有显著保护作用（逆方差加权法：p=0.017，OR=0.846，95%CI=0.737~0.971）。组织蛋白酶E可介导APBB1IP、NT5C3B及ZNF66对人表皮生长因子受体2阴性（human epidermal growth factor receptor 2 negative，HER2-negative）乳腺癌的调控效应，同时介导DHRS9、CDK12及CD247对人表皮生长因子受体2阳性（human epidermal growth factor receptor 2 positive，HER2-positive）乳腺癌的调控效应。组织蛋白酶F可介导ANXA2R与ZNF605对原位乳腺癌的调控效应。组织蛋白酶Z可介导PRX、CRY2、ADCY3及PELATON对原位乳腺癌的调控效应。
讨论 本研究结果凸显了组织蛋白酶在乳腺癌发生过程中兼具风险因子与保护因子的双重角色，进一步强调了其在乳腺癌诊断与治疗策略中的潜在应用前景。