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

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.

Fig. 1

Flowchart of the analyses performed.

Fig. 2

Mendelian randomization results for the association between the expression of druggable targets and breast cancer risk. ^aOdd ratios were calculated by the expectation of causal estimate (β coefficient). ^b‘Colocalization’ indicates PP.H4 between eQTLs and GWAS. PP.H4 > 0.8 is the well-applied cut-off for the evidence of colocalization.

Fig. 3

Mendelian randomization results for the association between druggable targets gene methylations and breast cancer risk. ^aOdd ratios were calculated by the expectation of causal estimate (β coefficient). ^b‘Colocalization’ indicates PP.H4 between mQTLs and GWAS. PP.H4 > 0.8 is the well-applied cut-off for the evidence of colocalization.

Fig. 4

Odds ratios and 95% confidence intervals of breast cancer associated with drug use among the Swedish population. ^aAdjusted for age, education, income, residence area, parity, obesity, chronic obstructive pulmonary disease, and Charlson Comorbidity Index score.