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Identifying therapeutic targets for breast cancer: insights from systematic Mendelian randomization analysis
Tao Yao1, Yun-Lu Lin1, Yu-Qing Wu1
1The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Background:
Breast cancer (BC) exhibits a high incidence rate, imposing a substantial burden on healthcare systems. Novel drug targets are urgently needed for BC. Mendelian randomization (MR) has gained widespread application for identifying fresh therapeutic targets. Our endeavor was to pinpoint circulatory proteins causally linked to BC risk and proffer potential treatment targets for BC.
Methods:
Through amalgamating protein quantitative trait loci from 2,004 circulating proteins and comprehensive genome-wide association study data from the Breast Cancer Association Consortium, we conducted MR analyses. Employing Steiger filtering, bidirectional MR, Bayesian colocalization, phenotype scanning, and replication analyses, we further solidified MR study outcomes. Additionally, protein-protein interaction (PPI) network was harnessed to unveil latent associations between proteins and prevailing breast cancer medications. The phenome-wide MR (Phe-MR) was employed to assess potential side effects and indications for the druggable proteins of BC. Finally, we further affirmed the drugability of potential drug targets through mRNA expression analysis and molecular docking.
Results:
Through comprehensive analysis, we identified five potential drug targets, comprising four (TLR1, A4GALT, SNUPN, and CTSF) for BC and one (TLR1) for BC_estrogen receptor positive. None of these five potential drug targets displayed reverse causation. Bayesian colocalization suggested that these five latent drug targets shared variability with breast cancer. All drug targets were replicated within the deCODE cohort. TLR1 exhibited PPI with current breast cancer therapeutic targets. Furthermore, Phe-MR unveiled certain adverse effects solely for TLR1 and SNUPN.
Conclusion:
Our study uncovers five prospective drug targets for BC and its subtypes, warranting further clinical exploration.
Insights
This study identified five potential drug targets for breast cancer (BC) and its subtypes using Mendelian randomization. These novel targets, including TLR1, offer promising avenues for future BC therapies and clinical investigation.
Area of Science:
- Genetics and Genomics
- Biochemistry
- Oncology
Background:
- Breast cancer (BC) presents a significant global health challenge due to its high incidence.
- There is a critical need for novel therapeutic targets to improve BC treatment outcomes.
- Mendelian randomization (MR) is an established method for identifying genetic factors associated with disease risk and potential drug targets.
Purpose of the Study:
- To identify circulating proteins causally associated with breast cancer risk.
- To discover novel protein targets for BC treatment.
- To evaluate the drugability and potential side effects of identified targets.
Main Methods:
- Utilized Mendelian randomization (MR) by integrating protein quantitative trait loci data with genome-wide association study data.
- Employed advanced MR techniques including Steiger filtering, bidirectional MR, and Bayesian colocalization for robust association analysis.
- Integrated protein-protein interaction (PPI) networks, phenome-wide MR (Phe-MR), mRNA expression analysis, and molecular docking to assess target validity and drugability.
Main Results:
- Identified five potential drug targets: TLR1, A4GALT, SNUPN, and CTSF for general BC, and TLR1 specifically for estrogen receptor-positive BC.
- Confirmed the causal link and shared variability between these targets and BC through rigorous MR analyses and replication in an independent cohort.
- TLR1 demonstrated interactions with existing BC therapeutic targets, and Phe-MR indicated potential adverse effects for TLR1 and SNUPN.
Conclusions:
- The study successfully identified five novel protein targets for breast cancer and its subtypes.
- These findings provide a strong foundation for further preclinical and clinical research into new BC therapies.
- The identified targets, particularly TLR1, represent promising candidates for drug development in breast cancer treatment.
