Multiple molecular subtypes of triple-negative breast cancer critically rely on androgen receptor and respond to enzalutamide in vivo.
Multiple molecular subtypes of triple-negative breast cancer critically rely on androgen receptor and respond to enzalutamide in vivo.
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三阴性乳腺癌的多个分子亚型批判性地依赖于雄激素受体，并在体内对enzalutamide反应。
DOI：
10.1158/1535-7163.mct-14-0926
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发表时间：
2015-03
影响因子：
5.7
通讯作者：
Richer JK
中科院分区：
文献类型：
--
作者：
Barton VN;D'Amato NC;Gordon MA;Lind HT;Spoelstra NS;Babbs BL;Heinz RE;Elias A;Jedlicka P;Jacobsen BM;Richer JK
三阴性乳腺癌（TNBC）具有浸润性乳腺癌的最低5年生存率，目前还没有针对这种侵袭性疾病的批准的靶向治疗。雄激素受体（AR）在多达三分之一的TNBC中表达，并且我们发现测试的所有AR + TNBC原发性肿瘤显示AR的核定位，指示转录活性受体。虽然AR在TNBC的"管腔AR（LAR）"分子亚型中最丰富，但在这里，我们首次使用新一代抗雄激素恩杂鲁胺和AR敲低两者来证明TNBC的其他非LAR分子亚型严重依赖于AR蛋白。事实上，AR抑制显著降低了四种TNBC系（SUM159PT、HCC 1806、BT549和MDA-MB-231）中的基线增殖、锚定非依赖性生长、迁移和侵袭，并增加了凋亡，这四种TNBC系代表三种非LAR TNBC分子亚型（间充质样、间充质干细胞样和基底样2）。在体内，Enzalutamide显著降低了SUM159PT和HCC 1806异种移植物的活力。此外，机制分析表明，AR激活上调EGFR配体双调蛋白（AREG）的分泌，Enzalutamide在体外和体内消除了这种作用。外源性AREG部分挽救了AR敲低对增殖、迁移和侵袭的影响，表明AREG的上调是AR影响致瘤性的一种机制。总之，我们的研究结果表明，TNBC的非LAR亚型具有AR依赖性，此外，Enzalutamide是AR + TNBC的多种分子亚型的有希望的靶向治疗。
Triple-negative breast cancer (TNBC) has the lowest 5-year survival rate of invasive breast carcinomas, and currently there are no approved targeted therapies for this aggressive form of the disease. The androgen receptor (AR) is expressed in up to one third of TNBC and we find that all AR+ TNBC primary tumors tested display nuclear localization of AR, indicative of transcriptionally active receptors. While AR is most abundant in the “luminal AR (LAR)” molecular subtype of TNBC, here, for the first time, we use both the new-generation anti-androgen enzalutamide and AR knockdown to demonstrate that the other non-LAR molecular subtypes of TNBC are critically dependent on AR protein. Indeed, AR inhibition significantly reduces baseline proliferation, anchorage-independent growth, migration, and invasion and increases apoptosis in four TNBC lines (SUM159PT, HCC1806, BT549, and MDA-MB-231), representing three non-LAR TNBC molecular subtypes (mesenchymal-like, mesenchymal stem–like, and basal-like 2). In vivo, enzalutamide significantly decreases viability of SUM159PT and HCC1806 xenografts. Furthermore, mechanistic analysis reveals that AR activation upregulates secretion of the EGFR ligand amphiregulin (AREG), an effect abrogated by enzalutamide in vitro and in vivo. Exogenous AREG partially rescues the effects of AR knockdown on proliferation, migration, and invasion, demonstrating that upregulation of AREG is one mechanism by which AR influences tumorigenicity. Together, our findings indicate that non-LAR subtypes of TNBC are AR dependent and, moreover, that enzalutamide is a promising targeted therapy for multiple molecular subtypes of AR+ TNBC.