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

Zhang, Naiqi LU ; Li, Yanni LU ; Sundquist, Jan LU ; Sundquist, Kristina LU and Ji, Jianguang LU orcid (2023) In EBioMedicine 98.
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... (More)

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.

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type
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publication status
published
subject
keywords
Breast cancer, Drug repositioning, Druggable target, Mendelian randomization, Population-based study
in
EBioMedicine
volume
98
article number
104859
publisher
Elsevier
external identifiers
  • pmid:38251461
  • scopus:85175008780
ISSN
2352-3964
DOI
10.1016/j.ebiom.2023.104859
language
English
LU publication?
yes
additional info
Funding Information: The authors wish to thank the Center for Primary Health Care Research's science editor Patrick O’Reilly for his valuable comments on the text. This work was supported by grants awarded to J.J. by the Swedish Research Council ( 2021-01187 ), 111 Project ( B21024 ), MAS cancer and Allmänna Sjukhusets i Malmö Stiftelsen för bekämpande av cancer; to K.S. by the Swedish Research Council as well as by ALF funding from Region Skåne; and to N.Z. by China Scholarship Council (Grant No. 201906380063 ). The funders of the study had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. Funding Information: Swedish Research Council, Cancerfonden, Crafoordska Stiftelsen, Allmänna Sjukhusets i Malmö Stiftelsen för bekämpande av cancer, 111 Project and MAS cancer.The authors wish to thank the Center for Primary Health Care Research's science editor Patrick O'Reilly for his valuable comments on the text. This work was supported by grants awarded to J.J. by the Swedish Research Council (2021-01187), 111 Project (B21024), MAS cancer and Allmänna Sjukhusets i Malmö Stiftelsen för bekämpande av cancer; to K.S. by the Swedish Research Council as well as by ALF funding from Region Skåne; and to N.Z. by China Scholarship Council (Grant No. 201906380063). The funders of the study had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. Publisher Copyright: © 2023 The Author(s)
id
6dbf931f-e9a1-485a-8858-7dfb18155ffd
date added to LUP
2023-11-05 09:25:30
date last changed
2024-04-19 03:34:27
@article{6dbf931f-e9a1-485a-8858-7dfb18155ffd,
  abstract     = {{<p>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.</p>}},
  author       = {{Zhang, Naiqi and Li, Yanni and Sundquist, Jan and Sundquist, Kristina and Ji, Jianguang}},
  issn         = {{2352-3964}},
  keywords     = {{Breast cancer; Drug repositioning; Druggable target; Mendelian randomization; Population-based study}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{EBioMedicine}},
  title        = {{Identifying actionable druggable targets for breast cancer : Mendelian randomization and population-based analyses}},
  url          = {{http://dx.doi.org/10.1016/j.ebiom.2023.104859}},
  doi          = {{10.1016/j.ebiom.2023.104859}},
  volume       = {{98}},
  year         = {{2023}},
}