Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
Cell Rep. 2023 Dec 26;42(12):113461. doi: 10.1016/j.celrep.2023.113461. Epub 2023 Nov 17.
Triple-negative breast cancer (TNBC) is an aggressive subtype with no targeted therapeutics. The luminal androgen receptor (LAR) subtype constitutes 15% of TNBC and is enriched for androgen receptor (AR) and AR target genes. Here, we show that a cohort of TNBC not only expresses AR at a much higher rate (∼80%) but also expresses AR splice variants (AR-SVs) (∼20%), further subclassifying LAR-TNBC. Higher AR and AR-SV expression and corresponding aggressive phenotypes are observed predominantly in specimens obtained from African American women. LAR TNBC specimens are enriched for interferon, Janus kinase (JAK)-signal activator and transducer (STAT), and androgen signaling pathways, which are exclusive to AR-expressing epithelial cancer cells. AR- and AR-SV-expressing TNBC cell proliferation and xenograft and patient-tumor explant growth are inhibited by AR N-terminal domain-binding selective AR degrader or by a JAK inhibitor. Biochemical analysis suggests that STAT1 is an AR coactivator. Collectively, our work identifies pharmacologically targetable TNBC subtypes and identifies growth-promoting interaction between AR and JAK-STAT signaling.
三阴性乳腺癌（TNBC）是一种侵袭性亚型，没有靶向治疗方法。腔面雄激素受体（LAR）亚型构成了 TNBC 的 15%，富含雄激素受体（AR）和 AR 靶基因。在这里，我们表明，一组 TNBC 不仅以更高的比率（80%）表达 AR，而且还表达 AR 剪接变体（AR-SVs）（20%），进一步对 LAR-TNBC 进行分类。更高的 AR 和 AR-SV 表达以及相应的侵袭性表型主要在来自非裔美国女性的标本中观察到。LAR TNBC 标本富含干扰素、Janus 激酶（JAK）-信号激活物和转导物（STAT）和雄激素信号通路，这些通路仅存在于表达 AR 的上皮癌细胞中。AR 和 AR-SV 表达的 TNBC 细胞增殖以及异种移植和患者肿瘤外植体生长均被 AR N 端结构域结合的选择性 AR 降解物或 JAK 抑制剂抑制。生化分析表明 STAT1 是 AR 的共激活剂。总的来说，我们的工作确定了可通过药理学靶向治疗的 TNBC 亚型，并确定了 AR 和 JAK-STAT 信号之间的促进生长的相互作用。
