Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer.
Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer.
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雄激素受体抑制对间充质干细胞样三阴性乳腺癌的抗增殖作用。
DOI：
10.1159/000443052
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Guan Xiaoxiang
中科院分区：
文献类型：
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作者：
Zhu Aiyu;Li Yan;Song Wei;Xu Yumei;Yang Fang;Zhang Wenwen;Yin Yongmei;Guan Xiaoxiang
雄激素受体（AR）是一种甾体激素受体，最近已成为乳腺癌预后和治疗预测的标志物。先前的研究表明，AR在高达三分之一的三阴性乳腺癌（TNBC）中广泛表达。然而，AR在TNBC中的作用仍不完全清楚，特别是在间充质干细胞样（MSL）TNBC cells.MethodsMSL TNBC MDA-MB-231和Hs 578 T乳腺癌细胞暴露于不同浓度的激动剂5-α-二氢睾酮（DHT）或非甾体拮抗剂比卡鲁胺或未经处理。采用MTT法、细胞计数法、流式细胞仪检测AR对细胞活力和凋亡的影响;采用Western blotting检测AR对p53、p73、p21和Cyclin D1蛋白表达的影响。ChIP法检测AR与p73和p21启动子的结合。方法：将MDA-MB-231细胞移植于裸鼠体内，分别用双氢睾酮（DHT）和比卡鲁胺（bicalutamide）处理后，测定肿瘤生长曲线，免疫组化（IHC）检测AR、p73和p21的表达。类似地，活化的AR显著增加体内MDA-MB-231异种移植物的存活力。相反，AR拮抗剂比卡鲁胺可引起细胞凋亡并对乳腺癌的生长产生抑制作用。此外，DHT依赖的AR激活涉及细胞周期相关基因的调节，包括p73，p21和Cyclin D1。进一步的研究表明，AR对p73和p21介导的AR直接结合到他们的启动子，和DHT可以使这些binding更effectively.ConclusionsOur study demonstrates the tumorgenesis role of AR and the inhibitory effect of bicutamide in AR-positive MSL TNBC in vitro and in vivo，提示AR抑制可能是一个潜在的治疗方法为AR-阳性TNBC patients.
Background/AimsAndrogen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells.MethodsMSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide.ResultsWe demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively.ConclusionsOur study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.