Androgen receptor-mediated pharmacogenomic expression quantitative trait loci: implications for breast cancer response to AR-targeting therapy.
Humans
Breast Neoplasms
/ genetics
Female
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Receptors, Androgen
/ genetics
Genome-Wide Association Study
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
/ drug effects
Dihydrotestosterone
/ pharmacology
Phenylthiohydantoin
/ pharmacology
Nitriles
/ therapeutic use
Genotype
Pharmacogenetics
/ methods
Pharmacogenomic Variants
Antineoplastic Agents, Hormonal
/ therapeutic use
Benzamides
Androgen receptor
Aromatase inhibitor
Breast cancer
Endocrine therapy
GWAS
PGx-eQTL
Pharmacogenomics
Journal
Breast cancer research : BCR
ISSN: 1465-542X
Titre abrégé: Breast Cancer Res
Pays: England
ID NLM: 100927353
Informations de publication
Date de publication:
04 Jul 2024
04 Jul 2024
Historique:
received:
17
11
2023
accepted:
20
06
2024
medline:
5
7
2024
pubmed:
5
7
2024
entrez:
4
7
2024
Statut:
epublish
Résumé
Endocrine therapy is the most important treatment modality of breast cancer patients whose tumors express the estrogen receptor α (ERα). The androgen receptor (AR) is also expressed in the vast majority (80-90%) of ERα-positive tumors. AR-targeting drugs are not used in clinical practice, but have been evaluated in multiple trials and preclinical studies. We performed a genome-wide study to identify hormone/drug-induced single nucleotide polymorphism (SNP) genotype - dependent gene-expression, known as PGx-eQTL, mediated by either an AR agonist (dihydrotestosterone) or a partial antagonist (enzalutamide), utilizing a previously well characterized lymphoblastic cell line panel. The association of the identified SNPs-gene pairs with breast cancer phenotypes were then examined using three genome-wide association (GWAS) studies that we have published and other studies from the GWAS catalog. We identified 13 DHT-mediated PGx-eQTL loci and 23 Enz-mediated PGx-eQTL loci that were associated with breast cancer outcomes post ER antagonist or aromatase inhibitors (AI) treatment, or with pharmacodynamic (PD) effects of AIs. An additional 30 loci were found to be associated with cancer risk and sex-hormone binding globulin levels. The top loci involved the genes IDH2 and TMEM9, the expression of which were suppressed by DHT in a PGx-eQTL SNP genotype-dependent manner. Both of these genes were overexpressed in breast cancer and were associated with a poorer prognosis. Therefore, suppression of these genes by AR agonists may benefit patients with minor allele genotypes for these SNPs. We identified AR-related PGx-eQTL SNP-gene pairs that were associated with risks, outcomes and PD effects of endocrine therapy that may provide potential biomarkers for individualized treatment of breast cancer.
Sections du résumé
BACKGROUND
BACKGROUND
Endocrine therapy is the most important treatment modality of breast cancer patients whose tumors express the estrogen receptor α (ERα). The androgen receptor (AR) is also expressed in the vast majority (80-90%) of ERα-positive tumors. AR-targeting drugs are not used in clinical practice, but have been evaluated in multiple trials and preclinical studies.
METHODS
METHODS
We performed a genome-wide study to identify hormone/drug-induced single nucleotide polymorphism (SNP) genotype - dependent gene-expression, known as PGx-eQTL, mediated by either an AR agonist (dihydrotestosterone) or a partial antagonist (enzalutamide), utilizing a previously well characterized lymphoblastic cell line panel. The association of the identified SNPs-gene pairs with breast cancer phenotypes were then examined using three genome-wide association (GWAS) studies that we have published and other studies from the GWAS catalog.
RESULTS
RESULTS
We identified 13 DHT-mediated PGx-eQTL loci and 23 Enz-mediated PGx-eQTL loci that were associated with breast cancer outcomes post ER antagonist or aromatase inhibitors (AI) treatment, or with pharmacodynamic (PD) effects of AIs. An additional 30 loci were found to be associated with cancer risk and sex-hormone binding globulin levels. The top loci involved the genes IDH2 and TMEM9, the expression of which were suppressed by DHT in a PGx-eQTL SNP genotype-dependent manner. Both of these genes were overexpressed in breast cancer and were associated with a poorer prognosis. Therefore, suppression of these genes by AR agonists may benefit patients with minor allele genotypes for these SNPs.
CONCLUSIONS
CONCLUSIONS
We identified AR-related PGx-eQTL SNP-gene pairs that were associated with risks, outcomes and PD effects of endocrine therapy that may provide potential biomarkers for individualized treatment of breast cancer.
Identifiants
pubmed: 38965614
doi: 10.1186/s13058-024-01861-2
pii: 10.1186/s13058-024-01861-2
doi:
Substances chimiques
Receptors, Androgen
0
Dihydrotestosterone
08J2K08A3Y
enzalutamide
93T0T9GKNU
Phenylthiohydantoin
2010-15-3
Nitriles
0
AR protein, human
0
Antineoplastic Agents, Hormonal
0
Benzamides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
111Subventions
Organisme : Regis Foundation Mayo Clinic Center for Individualized Medicine
ID : MC1351
Organisme : Breast Cancer Research Foundation
ID : BCRF-22-076
Organisme : Mayo Clinic Breast Cancer Specialized Program of Research Excellence Grant
ID : P50CA 116201
Informations de copyright
© 2024. The Author(s).
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