Ligand-dependent genomic function of glucocorticoid receptor in triple-negative breast cancer.
Ligand-dependent genomic function of glucocorticoid receptor in triple-negative breast cancer.
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DOI：
10.1038/ncomms9323
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发表时间：
2015-09-16
影响因子：
16.6
通讯作者：
Wang Q
中科院分区：
文献类型：
--
作者：
Chen Z;Lan X;Wu D;Sunkel B;Ye Z;Huang J;Liu Z;Clinton SK;Jin VX;Wang Q
糖皮质激素（GC）已广泛用作实体瘤治疗的辅助剂，但GC治疗可能与不良的药物治疗反应或预后相关。 GC 在这些肿瘤中的基因组作用很大程度上未知。在这里，我们发现三阴性乳腺癌（TNBC）细胞中的地塞米松（Dex，一种合成GC）调节基因与耐药性相关。重要的是，这些 GC 调节的基因在 TNBC 患者中异常表达，并与不良的临床结果相关。有趣的是，在TNBC细胞中，化合物A（CpdA，一种选择性GR调节剂）仅调节少数不参与致癌和治疗耐药的基因。使用 ChIP-exo 方法进行的机制研究表明，Dex 配体的糖皮质激素受体 (GR) 与单个糖皮质激素反应元件 (GRE) 结合，而 CpdA 配体的糖皮质激素受体 (GR) 则不然，从而驱动促肿瘤基因的表达。我们的数据表明，安全辅助治疗的开发应考虑 Dex 配体 GR 和 CpdA 配体 GR 之间不同的基因组功能。 糖皮质激素广泛用作实体瘤治疗的辅助剂。在这里，陈等人。研究表明，受地塞米松而非化合物 A 配体糖皮质激素受体调节的基因与三阴性乳腺癌的治疗耐药性和不良临床结果相关。
Glucocorticoids (GCs) have been widely used as coadjuvants in the treatment of solid tumours, but GC treatment may be associated with poor pharmacotherapeutic response or prognosis. The genomic action of GC in these tumours is largely unknown. Here we find that dexamethasone (Dex, a synthetic GC)-regulated genes in triple-negative breast cancer (TNBC) cells are associated with drug resistance. Importantly, these GC-regulated genes are aberrantly expressed in TNBC patients and are associated with unfavourable clinical outcomes. Interestingly, in TNBC cells, Compound A (CpdA, a selective GR modulator) only regulates a small number of genes not involved in carcinogenesis and therapy resistance. Mechanistic studies using a ChIP-exo approach reveal that Dex- but not CpdA-liganded glucocorticoid receptor (GR) binds to a single glucocorticoid response element (GRE), which drives the expression of pro-tumorigenic genes. Our data suggest that development of safe coadjuvant therapy should consider the distinct genomic function between Dex- and CpdA-liganded GR. Glucocorticoids are widely used as coadjuvants in the treatment of solid tumours. Here, Chen et al. show that genes regulated by dexamethasone- but not Compound A-liganded glucocorticoid receptor are associated with therapy resistance and unfavourable clinical outcomes in triple-negative breast cancer.