澳大利亚阿德莱德大学Wayne D. Tilley研究组近日取得一项新成果。他们的最新研究提出雄激素受体（AR）是雌激素受体（ER）阳性乳腺癌的抑癌药。2021年1月18日出版的《自然-医学》杂志发表了这项成果。

他们使用了多种多样的、临床相关细胞系模型和患者来源模型，证明了AR激活而不是抑制在多种疾病中发挥了有效的抗肿瘤活性，包括对标准治疗ER和CDK4 / 6抑制剂的抵抗力。值得注意的是，AR激动剂与护理标准药物联合使用可增强治疗反应。

从机理上讲，AR的激动剂激活改变了ER和必需的共激活因子（p300，SRC-3）的基因组分布，导致ER调控的细胞周期基因被抑制，AR靶基因（包括已知的肿瘤抑制因子）被上调。 AR活性的基因标志肯定预测多个临床ER阳性乳腺癌队列中的疾病生存。

这些发现提供了明确的证据，即AR在ER阳性乳腺癌中具有抑癌作用，并支持AR激动作为最佳的AR导向治疗策略，从而揭示了合理的治疗机会。

据悉，AR在ER-α阳性乳腺癌中的作用是有争议的，从而限制了AR定向疗法的实施。

附：英文原文

Title: The androgen receptor is a tumor suppressor in estrogen receptor–positive breast cancer

Author: Theresa E. Hickey, Luke A. Selth, Kee Ming Chia, Geraldine Laven-Law, Heloisa H. Milioli, Daniel Roden, Shalini Jindal, Mun Hui, Jessica Finlay-Schultz, Esmaeil Ebrahimie, Stephen N. Birrell, Suzan Stelloo, Richard Iggo, Sarah Alexandrou, C. Elizabeth Caldon, Tarek M. Abdel-Fatah, Ian O. Ellis, Wilbert Zwart, Carlo Palmieri, Carol A. Sartorius, Alex Swarbrick, Elgene Lim, Jason S. Carroll, Wayne D. Tilley

Issue&Volume: 2021-01-18

Abstract: 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. Functional interplay of sex hormones in estrogen receptor–positive breast cancer unveils the therapeutic potential of androgen receptor agonists.

DOI: 10.1038/s41591-020-01168-7

Source: https://www.nature.com/articles/s41591-020-01168-7