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中华临床医师杂志(电子版) ›› 2022, Vol. 16 ›› Issue (11) : 1031 -1038. doi: 10.3877/cma.j.issn.1674-0785.2022.11.001

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雄激素受体在乳腺癌应用中的探索之路
李嘉颐1, 张虹2, 叶京明1, 刘荫华1, 徐玲1,†(), 张爽2,†()   
  1. 1. 100034　北京，北京大学第一医院乳腺疾病中心
    2. 100034　北京，北京大学第一医院病理科
  • 收稿日期:2022-01-07 出版日期:2022-11-15
  • 通信作者: 徐玲, 张爽

Androgen receptor: discoveries in breast cancer clinical practice

Jiayi Li1, Hong Zhang2, Jingming Ye1, Yinhua Liu1, Ling Xu1,†(), Shuang Zhang2,†()   

  1. 1. Breast Disease Center, Peking University First Hospital, Beijing 100034, China
    2. Department of Pathology, Peking University First Hospital, Beijing 100034, China
  • Received:2022-01-07 Published:2022-11-15
  • Corresponding author: Ling Xu, Shuang Zhang
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引用本文：

李嘉颐, 张虹, 叶京明, 刘荫华, 徐玲, 张爽. 雄激素受体在乳腺癌应用中的探索之路[J]. 中华临床医师杂志(电子版), 2022, 16(11): 1031-1038.

Jiayi Li, Hong Zhang, Jingming Ye, Yinhua Liu, Ling Xu, Shuang Zhang. Androgen receptor: discoveries in breast cancer clinical practice[J]. Chinese Journal of Clinicians(Electronic Edition), 2022, 16(11): 1031-1038.

乳腺癌是世界范围内发病率最高的恶性肿瘤，目前乳腺癌治疗已进入以分子标志物为指导的分类治疗时代。雄激素受体（AR）是乳腺癌中常见的分子标志物，对乳腺癌细胞活动起调控作用。在临床中，AR表达与乳腺癌患者预后存在一定相关性。AR靶向治疗和相关联合治疗正处于研究中。本文通过查阅近年来相关文献，分别从AR的作用机制、表达与临床价值、相关治疗等方面对AR在乳腺癌应用中的探索进行综述。

关键词: 乳腺肿瘤, 乳腺癌, 分子分型, 雄激素受体, 预后, 雄激素受体靶向治疗

Breast cancer is the malignant tumor with the highest incidence in the world. At present, breast cancer treatment has entered the era of classified treatment guided by molecular markers. Androgen receptor (AR) is a commonly expressed molecular marker in breast cancer, which regulates breast cancer cell activities. In clinical practice, AR expression has an appreciated correlation with the prognosis of breast cancer patients, and AR-targeted therapy and related combination therapies are under investigation. This article summarizes the application of AR in breast cancer from the aspects of mechanism, expression and clinical value, and related therapies, by reviewing the relevant literature in recent years.

Key words: Breast neoplasms, Breast cancer, Molecular subtype, Androgen receptor, Prognosis, Androgen receptor targeted therapy
图1 乳腺癌中AR活化机制及相关药物靶点 在雄激素信号通路经典途径中，AR与DHT结合，转移到细胞核内并与ARE结合，激活基因表达。在非经典途径中，mAR与DHT结合，通过磷脂酰肌醇3-激酶/蛋白激酶B/哺乳动物类雷帕霉素靶蛋白（PI3K/AKT/mTOR）和Ras/Raf/丝裂原活化蛋白激酶/细胞外调节蛋白激酶（Ras/Raf/MAPK/ERK）通路激活基因表达。比卡鲁胺能阻断AR与ARE的结合；恩杂鲁胺干扰AR向核内移动；CYP17A酶抑制剂阻断DHT生成。SARM能与AR结合并调控细胞活动注：AR为雄激素受体；HSP为热休克蛋白；DHT为双氢睾酮；ARE为雄激素反应区段；FOXA1为叉头框蛋白A1；mAR为膜相关雄激素受体；SARM为选择性雄激素受体调节剂；PTEN为第10号染色体缺失的磷酸酶及张力蛋白同源的基因
表1 雄激素受体（AR）靶向治疗药物及相关临床研究
药物 药物机制 研究代码 入组人群 治疗方案 研究结果
比卡鲁胺 第一代非甾体AR拮抗剂，通过干扰雄激素-AR复合物与DNA结合产生作用。 NCT00468715［60］ ER/PR阴性晚期乳腺癌，AR＞10%（n=26） 比卡鲁胺 6月CBR 19%，中位PFS 12周
NCT02910050［61］ 接受过AI治疗的ER+AR+HER-2-转移性乳腺癌（n=18） 比卡鲁胺+AI 6月CBR 16.7%，中位PFS 2.7个月
恩杂鲁胺 第二代非甾体AR拮抗剂，通过干扰雄激素-AR复合物向细胞核内转移、染色质结合、调控因子发挥作用。 NCT01889238［62］ 局部进展和远处转移AR阳性（＞0%）TNBC（n=78） 恩杂鲁胺

16周CBR 25%，中位PFS 2.9个月，中位OS 12.7个月；AR≥10%

亚组：16周CBR 33%，中位PFS 3.3个月，中位OS 17.6个月

NCT02457910

（TBCRC032）［63］

 AR≥10%的转移性TNBC（n=12） 恩杂鲁胺+taselisib 16周CBR 35.7%，中位PFS 3.4个月
NCT02007512［64］ HR+HER-2正常晚期/转移性乳腺癌（n=247） 实验组：依西美坦+恩杂鲁胺，对照组：依西美坦+安慰剂 既往无内分泌治疗组：24周CBR 62%比45%，PFS 11.8个月比5.8个月；既往内分泌治疗组：24周CBR 20%比32%，PFS 3.6个月比3.9个月
NCT02091960［65］ HER-2+AR+乳腺癌（n=89） 恩杂鲁胺+曲妥珠单抗 24周CBR 24%，中位PFS 3.4个月
阿比特龙 CYP17A酶抑制剂，通过抑制CYP17A酶活性阻断DHT生成，目前被用于去势抵抗性前列腺癌治疗。 NCT01381874［66］ ER+晚期乳腺癌（n=297） AA组：阿比特龙，AAE组：阿比特龙+依西美坦，E组依西美坦 PFS：AA组3.7个月，AAE组4.5个月，E组3.7个月，无显著差异
NCT01842321［67］ 远处转移或局部进展的AR+（≥10%）TNBC（n=30） 阿比特龙 6个月CBR 20.0%，ORR 6.7%，中位PFS 2.8个月
Enobosarm SARM，与AR复合后向细胞核转移后，作为转录调节剂并募集辅助因子和核心蛋白，调节相关转录反应，产生AR激动作用。 NCT 02971761［68］ AR+（≥10%）远处转移TNBC（n=18） Enobosarm+帕博利珠单抗 16周CBR 25%，中位PFS 2.6个月，OS 25.5个月
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