内分泌治疗是肿瘤表达雌激素受体α（ERα）的乳腺癌患者最重要的治疗方式。雄激素受体 (AR) 也在绝大多数 (80-90%) ERα 阳性肿瘤中表达。 AR靶向药物尚未用于临床实践，但已在多项试验和临床前研究中进行了评估。我们进行了一项全基因组研究，以确定激素/药物诱导的单核苷酸多态性（SNP）基因型依赖性基因表达，已知作为 PGx-eQTL，由 AR 激动剂（二氢睾酮）或部分拮抗剂（恩杂鲁胺）介导，利用先前充分表征的淋巴细胞系组。然后使用我们已发表的三项全基因组关联 (GWAS) 研究以及 GWAS 目录中的其他研究检查已确定的 SNP 基因对与乳腺癌表型的关联。我们确定了 13 个 DHT 介导的 PGx-eQTL 位点和 23 个Enz 介导的 PGx-eQTL 位点与 ER 拮抗剂或芳香酶抑制剂 (AI) 治疗后的乳腺癌结局相关，或与 AI 的药效 (PD) 效应相关。另外 30 个位点被发现与癌症风险和性激素结合球蛋白水平相关。顶部位点涉及基因 IDH2 和 TMEM9，其表达以 PGx-eQTL SNP 基因型依赖性方式被 DHT 抑制。这两种基因在乳腺癌中都过度表达，并且与较差的预后相关。因此，通过 AR 激动剂抑制这些基因可能会使这些 SNP 具有较小等位基因基因型的患者受益。我们鉴定了与 AR 相关的 PGx-eQTL SNP 基因对，这些基因对与内分泌治疗的风险、结果和 PD 效应相关，可能提供潜在的生物标志物用于乳腺癌的个体化治疗。© 2024。作者。

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.© 2024. The Author(s).