Identifying actionable druggable targets for breast cancer: Mendelian randomization and population-based analyses

Naiqi Zhang; Yanni Li; Jan Sundquist; Kristina Sundquist; Jianguang Ji

doi:10.1016/j.ebiom.2023.104859

Identifying actionable druggable targets for breast cancer: Mendelian randomization and population-based analyses

EBioMedicine. 2023 Dec:98:104859. doi: 10.1016/j.ebiom.2023.104859. Epub 2023 Oct 28.

Authors

Naiqi Zhang¹, Yanni Li², Jan Sundquist³, Kristina Sundquist³, Jianguang Ji²

Affiliations

¹ Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Sweden. Electronic address: naiqi.zhang@med.lu.se.
² Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Sweden.
³ Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Sweden; Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, USA; Center for Community-based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Japan.

Abstract

Background: Drug repurposing provides a cost-effective approach to address the need for breast cancer prevention and therapeutics. We aimed to identify actionable druggable targets using Mendelian randomization (MR) and then validate the candidate drugs using population-based analyses.

Methods: We identified genetic instruments for 1406 actionable targets of approved non-oncological drugs based on gene expression, DNA methylation, and protein expression quantitative trait loci (eQTL, mQTL, and pQTL, respectively). Genome-wide association study (GWAS) summary statistics were obtained from the Breast Cancer Association Consortium (122,977 cases, 105,974 controls). We further conducted a nested case-control study using data retrieved from Swedish registers to validate the candidate drugs that were identified from MR analyses.

Findings: We identified six significant MR associations with gene expression levels (TUBB, MDM2, CSK, ULK3, MC1R and KCNN4) and two significant associations with gene methylation levels across 21 CpG islands (RPS23 and MAPT). Results from the nested case-control study showed that the use of raloxifene (targeting MAPT) was associated with 35% reduced breast cancer risk (odds ratio, OR, 0.65; 95% confidence interval, CI, 0.51-0.83). However, usage of estradiol, tolterodine, and nitrofurantoin (also targeting MAPT) was associated with increased breast cancer risk, with adjusted ORs and 95% CI of 1.10 (1.07-1.13), 1.16 (1.09-1.24), and 1.09 (1.05-1.13), respectively. The effect of raloxifene and nitrofurantoin lost significance in further validation analyses using active-comparator and new-user design.

Interpretation: This large-scale MR analysis, combined with population-based validation, identified eight druggable target genes for breast cancer and suggested that raloxifene is an effective chemoprevention against breast cancer.

Funding: Swedish Research Council, Cancerfonden, Crafoordska Stiftelsen, Allmänna Sjukhusets i Malmö Stiftelsen för bekämpande av cancer, 111 Project and MAS cancer.

Keywords: Breast cancer; Drug repositioning; Druggable target; Mendelian randomization; Population-based study.

MeSH terms

Breast Neoplasms* / drug therapy
Breast Neoplasms* / genetics
Case-Control Studies
Female
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis
Nitrofurantoin
Raloxifene Hydrochloride / pharmacology
Raloxifene Hydrochloride / therapeutic use

Substances

Nitrofurantoin
Raloxifene Hydrochloride