Oh Tae Gyu, Wang Shu-Ching M, Acharya Bipul R, Goode Joel M, Graham J Dinny, Clarke Christine L, Yap Alpha S, Muscat George E O
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
Westmead Millennium Institute, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
EBioMedicine. 2016 Apr;6:59-72. doi: 10.1016/j.ebiom.2016.02.028. Epub 2016 Feb 18.
We have previously reported that RORγ expression was decreased in ER-ve breast cancer, and increased expression improves clinical outcomes. However, the underlying RORγ dependent mechanisms that repress breast carcinogenesis have not been elucidated. Here we report that RORγ negatively regulates the oncogenic TGF-β/EMT and mammary stem cell (MaSC) pathways, whereas RORγ positively regulates DNA-repair. We demonstrate that RORγ expression is: (i) decreased in basal-like subtype cancers, and (ii) inversely correlated with histological grade and drivers of carcinogenesis in breast cancer cohorts. Furthermore, integration of RNA-seq and ChIP-chip data reveals that RORγ regulates the expression of many genes involved in TGF-β/EMT-signaling, DNA-repair and MaSC pathways (including the non-coding RNA, LINC00511). In accordance, pharmacological studies demonstrate that an RORγ agonist suppresses breast cancer cell viability, migration, the EMT transition (microsphere outgrowth) and mammosphere-growth. In contrast, RNA-seq demonstrates an RORγ inverse agonist induces TGF-β/EMT-signaling. These findings suggest pharmacological modulation of RORγ activity may have utility in breast cancer.
我们之前报道过，在雌激素受体阴性（ER-ve）乳腺癌中，RORγ表达降低，而其表达增加可改善临床结局。然而，抑制乳腺癌发生的潜在RORγ依赖性机制尚未阐明。在此我们报道，RORγ对致癌性转化生长因子-β/上皮-间质转化（TGF-β/EMT）和乳腺干细胞（MaSC）通路起负调控作用，而对DNA修复起正调控作用。我们证明，RORγ表达在以下情况中降低：（i）在基底样亚型癌症中；（ii）在乳腺癌队列中与组织学分级和致癌驱动因素呈负相关。此外，RNA测序（RNA-seq）和染色质免疫沉淀芯片（ChIP-chip）数据整合显示，RORγ调节许多参与TGF-β/EMT信号传导、DNA修复和MaSC通路的基因表达（包括非编码RNA，LINC00511）。相应地，药理学研究表明，RORγ激动剂可抑制乳腺癌细胞活力、迁移、EMT转变（微球生长）和乳腺球生长。相反，RNA-seq显示RORγ反向激动剂可诱导TGF-β/EMT信号传导。这些发现表明，对RORγ活性进行药理学调节可能对乳腺癌治疗有用。
