外乳头 Paget 病（EMPD）是一种罕见的上皮内腺癌，主要影响肛门、生殖器和腋窝区域。尽管其病因尚未完全阐明，但有证据表明雄激素受体（AR）在大多数 EMPD 患者中表达。然而，雄激素信号在 EMPD 发病机制中的作用仍不清楚。为了评估雄激素信号在 AR 阳性 EMPD 肿瘤生长中的作用，我们建立了来自两个 AR 阳性 EMPD 患者（一男一女）的患者源器官样团体，进行了培养。文化的器官样团体接受了雄激素激动剂和/或拮抗剂的处理，然后进行有关器官样团体增殖变化以及雄激素信号通路特异基因变化的分析。我们从每个 EMPD 样品建立了器官样团体培养。这些器官样团体在免疫组织化学和基因上均与原始肿瘤相同。对于每个器官样团体样本，可存活细胞数在接受雄激素暴露后增加。已知 AR 靶基因 Fkbp5 的 mRNA 水平在接受合成雄激素 R1881 暴露的器官样团体中呈浓度依赖性增加。相反，AR 抑制剂 darolutamide 在浓度依赖性地抑制可存活细胞数。而 darolutamide 也抑制了 MKI67 和 Fkbp5 的 mRNA 表达水平。我们的结果表明，雄激素信号是 AR 阳性 EMPD 生长的关键途径。因此，雄激素信号抑制可能是 EMPD 患者需要全身治疗的新型治疗选择。 版权所有 © 2023。由 Elsevier B.V. 发布。

Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma that mainly affects the anogenital and axillary regions. Although its etiology has not been fully elucidated, there is evidence that androgen receptors (AR) are expressed in most cases of EMPD. However, the role of androgen signaling in the pathogenesis of EMPD remains unclear.To evaluate the role of androgen signaling in tumor growth of AR-positive EMPD.Patient-derived organoids were established and cultured from two AR-positive EMPD patients: one man and one woman. Cultured organoids were treated with androgen agonists and/or antagonists, then subjected to analysis of changes in organoid proliferation, as well as changes in androgen signaling pathway-specific genes.Organoid cultures were established from each EMPD sample. These organoids were immunohistologically and genetically identical to the original tumor. For each organoid sample, viable cell number increased in response to androgen exposure. The mRNA level of Fkbp5, a known AR target gene, increased in a concentration-dependent manner in organoids exposed to the synthetic androgen R1881. Conversely, the AR inhibitor darolutamide suppressed the viable cell number in a concentration-dependent manner. The mRNA expression levels of MKI67 and Fkbp5 were also suppressed by darolutamide.Our results indicate that androgen signaling is a key pathway involved in the growth of AR-positive EMPD. Therefore, androgen signaling inhibition may be a novel treatment option for EMPD patients who require systemic therapy.Copyright © 2023. Published by Elsevier B.V.