The Nuclear Receptor, RORγ, Regulates Pathways Necessary for Breast Cancer Metastasis

We have previously reported that ROR gamma expression was decreased in ER-ve breast cancer, and increased expression improves clinical outcomes. However, the underlying ROR gamma dependent mechanisms that repress breast carcinogenesis have not been elucidated. Here we report that ROR gamma negatively regulates the oncogenic TGF-beta/EMT and mammary stem cell (MaSC) pathways, whereas ROR gamma positively regulates DNA-repair. We demonstrate that ROR gamma 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 ROR gamma regulates the expression of many genes involved in TGF-beta/EMT-signaling, DNA-repair and MaSC pathways (including the non-coding RNA, LINC00511). In accordance, pharmacological studies demonstrate that an ROR gamma agonist suppresses breast cancer cell viability, migration, the EMT transition (microsphere outgrowth) and mammosphere-growth. In contrast, RNA-seq demonstrates an ROR gamma inverse agonist induces TGF-beta/EMT-signaling. These findings suggest pharmacological modulation of ROR gamma activity may have utility in breast cancer. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).