The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.

雄激素受体 (AR) 在雌激素受体 (ER)-α 阳性乳腺癌中的作用存在争议，限制了 AR 导向疗法的实施。使用多样化的、临床相关的细胞系和患者来源的模型，我们证明 AR 激活（而不是抑制）在多种疾病环境中发挥有效的抗肿瘤活性，包括对标准护理 ER 和 CDK4/6 抑制剂的耐药性。值得注意的是，AR 激动剂与标准护理药物相结合可增强治疗反应。从机制上讲，AR 的激动剂激活改变了 ER 和必需共激活因子（p300、SRC-3）的基因组分布，导致 ER 调节的细胞周期基因的抑制和 AR 靶基因（包括已知的肿瘤抑制基因）的上调。 AR 活性的基因特征可以积极预测多个临床 ER 阳性乳腺癌队列的疾病生存率。这些发现提供了明确的证据，证明 AR 在 ER 阳性乳腺癌中具有肿瘤抑制作用，并支持 AR 激动作为最佳的 AR 导向治疗策略，揭示了合理的治疗机会。