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

• RORγ mRNA expression is decreased in the aggressive basal-like subtype and histological grade 3 breast cancers.
• RORγ expression negatively regulates TGF-β/EMT and MaSC pathways, and positively regulates the DNA-repair pathway.
• Agonists of RORγ activity display (in vitro) pharmacological utility against breast cancer.We have demonstrated that the expression of the druggable and hormone dependent DNA binding protein, the nuclear receptor, RORγ, is decreased in aggressive basal like and histological grade 3 human breast cancers. We then examined the role of RORγ in breast cancer and identified that RORγ: (i) negatively regulates pathways including TGF-β/EMT and mammary stem cell (MaSC)-pathways, that control cell invasion and immortalization, respectively, and (ii) positively regulates pathways necessary for repair of DNA damage. Lastly, we demonstrated that increasing RORγ activity with small molecules (in cells) displays pharmacological utility, suggesting that RORγ could be a target for breast cancer treatment.

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.

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