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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	104859
Journal	EBioMedicine
Volume	98
DOIs	https://doi.org/10.1016/j.ebiom.2023.104859
Publication status	Published - 2023 Dec

Bibliographical note

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)

Subject classification (UKÄ)

Medical Genetics
Cancer and Oncology

Free keywords

Breast cancer
Drug repositioning
Druggable target
Mendelian randomization
Population-based study

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ebiom.2023.104859Licence: CC BY-NC-ND

Cite this

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title = "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, Allm{\"a}nna Sjukhusets i Malm{\"o} Stiftelsen f{\"o}r bek{\"a}mpande av cancer, 111 Project and MAS cancer.",

keywords = "Breast cancer, Drug repositioning, Druggable target, Mendelian randomization, Population-based study",

author = "Naiqi Zhang and Yanni Li and Jan Sundquist and Kristina Sundquist and Jianguang Ji",

note = "Funding Information: The authors wish to thank the Center for Primary Health Care Research's science editor Patrick O{\textquoteright}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 Allm{\"a}nna Sjukhusets i Malm{\"o} Stiftelsen f{\"o}r bek{\"a}mpande av cancer; to K.S. by the Swedish Research Council as well as by ALF funding from Region Sk{\aa}ne; 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, Allm{\"a}nna Sjukhusets i Malm{\"o} Stiftelsen f{\"o}r bek{\"a}mpande 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 Allm{\"a}nna Sjukhusets i Malm{\"o} Stiftelsen f{\"o}r bek{\"a}mpande av cancer; to K.S. by the Swedish Research Council as well as by ALF funding from Region Sk{\aa}ne; 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: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = dec,

doi = "10.1016/j.ebiom.2023.104859",

language = "English",

volume = "98",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

}

TY - JOUR

T1 - Identifying actionable druggable targets for breast cancer

T2 - Mendelian randomization and population-based analyses

AU - Zhang, Naiqi

AU - Li, Yanni

AU - Sundquist, Jan

AU - Sundquist, Kristina

AU - Ji, Jianguang

N1 - 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)

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Drug repositioning

KW - Druggable target

KW - Mendelian randomization

KW - Population-based study

U2 - 10.1016/j.ebiom.2023.104859

DO - 10.1016/j.ebiom.2023.104859

M3 - Article

C2 - 38251461

AN - SCOPUS:85175008780

SN - 2352-3964

VL - 98

JO - EBioMedicine

JF - EBioMedicine

M1 - 104859

ER -

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

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

Access to Document

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Cite this