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Updated: Jun 6, 2025
Orthotopic Transplantation of Breast Tumors as Preclinical Models for Breast Cancer
Published on: May 18, 2020
Drug repurposing opportunities for breast cancer and seven common subtypes
Yilong Lin1, Songsong Wang2, Yun Zhang3
1Department of Breast Surgery, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China; School of Medicine, Xiamen University, Xiamen, China.
Abstract:
Breast cancer is a substantial global health problem, and drug repurposing provides novel opportunities to address the urgent need for therapeutics. According to significant Mendelian randomization (MR) results, we identified 26 genes for overall breast cancer, 25 genes for ER+ breast cancer and 4 genes (CASP8, KCNN4, MYLK4, TNNT3) for ER- breast cancer. In order to explore the differences between 5 intrinsic subtypes, we found 29 actionable druggable genes for Luminal A breast cancer, 2 genes (IGF2 and TNNT3) for Luminal B breast cancer, 1 gene (FAAH) for Luminal B HER2 negative breast cancer, and 3 genes (CASP8, KCNN4, and TP53) for triple-negative breast cancer. After colocalization analysis, we determined OPRL1 as a prioritized target in both overall and Luminal A breast cancer. Additionally, FES and FAAH were considered prioritized targets for ER+ breast cancer. Through molecular docking, crizotinib stand out as a prioritized FES target drug repurposing opportunity with the lowest binding energy (-10.13 kJ·mol-1) and CCK-8 assay showed ER+ cell groups were more sensitive to crizotinib than ER- cell groups. In conclusion, OPRL1 was identified as a prioritized target for both overall and Luminal A breast cancer. Moreover, FES and FAAH were recognized as prioritized targets for ER+ breast cancer.
Insights
Drug repurposing identified key genes for breast cancer subtypes. OPRL1 is a prioritized target for overall and Luminal A breast cancer, while FES and FAAH are targets for ER+ breast cancer.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Breast cancer poses a significant global health challenge.
- Drug repurposing offers a promising avenue for developing novel therapeutics.
- Identifying druggable targets is crucial for advancing breast cancer treatment.
Purpose of the Study:
- To identify actionable, druggable genes associated with various breast cancer subtypes using Mendelian randomization.
- To pinpoint prioritized therapeutic targets for overall, ER-positive, ER-negative, and intrinsic breast cancer subtypes.
- To explore drug repurposing opportunities for identified targets, including molecular docking and cell-based assays.
Main Methods:
- Mendelian randomization (MR) analysis to identify genetic associations with breast cancer.
- Colocalization analysis to prioritize genetic targets.
- Molecular docking simulations to evaluate drug-target interactions.
- CCK-8 assays to assess drug sensitivity in different breast cancer cell groups.
Main Results:
- Identified 26 genes for overall breast cancer, 25 for ER+ breast cancer, and 4 for ER- breast cancer.
- Discovered actionable druggable genes for intrinsic subtypes: Luminal A (29), Luminal B (2), Luminal B HER2 negative (1), and triple-negative (3).
- Prioritized OPRL1 for overall and Luminal A breast cancer; FES and FAAH for ER+ breast cancer. Crizotinib emerged as a potential repurposed drug for FES targets.
Conclusions:
- OPRL1 is a key prioritized target for both overall and Luminal A breast cancer.
- FES and FAAH are identified as prioritized targets for ER+ breast cancer.
- Drug repurposing, exemplified by crizotinib for FES, shows potential for novel breast cancer therapeutics.
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