The Androgen Receptor is a Tumor Suppressor in Estrogen Receptor Positive Breast Cancer [ZR-75-1 cell line Bicalutamide study ER ChIP-seq]. The Androgen Receptor is a Tumor Suppressor in Estrogen Receptor Positive Breast Cancer [ZR-75-1 cell line Bicalutamide study ER ChIP-seq]

The role of the androgen receptor (AR) in estrogen receptor alpha (ER) 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 anti-tumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Importantly, 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 up-regulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER+ breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER+ breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity. Overall design: ChIP-seq for ERα in ZR-75-1 cells cultured in steroid-depleted conditions and treated for 6 hours with Vehicle, 1 nM E2, 1 µM Bicalutamide, E2 + Bicalutamide, or E2 + 1 nM DHT. Bicalutamide was added 1 h prior to any hormone addition.

雄激素受体（androgen receptor, AR）在雌激素受体α（ER）阳性乳腺癌中的作用尚存争议，这一现状制约了AR靶向治疗的临床应用。本研究依托涵盖细胞系与患者来源模型的多样化临床相关模型库，证实AR激活而非抑制可在多种疾病情境中发挥强效抗肿瘤活性，包括对抗标准治疗方案下ER靶向药物与CDK4/6抑制剂的耐药性。值得注意的是，AR激动剂与标准治疗药物联合使用可显著增强治疗应答效果。从机制层面而言，AR激动剂激活可改变ER与关键共激活因子（p300、SRC-3）的基因组分布，进而抑制ER调控的细胞周期基因表达，并上调AR靶基因（包括已证实的肿瘤抑制基因）的转录水平。AR活性相关基因特征可在多个临床ER阳性乳腺癌队列中正向预测患者的疾病生存期。本研究结果明确证实AR在ER阳性乳腺癌中发挥肿瘤抑制因子的作用，并支持AR激动疗法为最优的AR靶向治疗策略，同时揭示了一项极具潜力的治疗契机。实验整体设计：对在类固醇剥夺培养基中培养的ZR-75-1细胞进行染色质免疫沉淀测序（ChIP-seq），细胞分别经以下处理：仅溶剂对照、1 nM雌二醇（E2）、1 μM比卡鲁胺（Bicalutamide）、E2联合比卡鲁胺，或E2联合1 nM二氢睾酮（DHT）。其中比卡鲁胺需在激素处理前1小时预先加入。