title: The Nuclear Receptor, RORγ, Regulates Pathways Necessary for Breast Cancer Metastasis.
abstract: 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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Tae Gyu
authors.initials: TG
authors.lastname: Oh
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Shu-Ching M
authors.initials: SM
authors.lastname: Wang
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Bipul R
authors.initials: BR
authors.lastname: Acharya
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Goode
authors.affiliation: Westmead Millennium Institute, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: J Dinny
authors.initials: JD
authors.lastname: Graham
authors.affiliation: Westmead Millennium Institute, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Clarke
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Alpha S
authors.initials: AS
authors.lastname: Yap
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia. Electronic address: g.muscat@uq.edu.au.
authors.forename: George E O
authors.initials: GEO
authors.lastname: Muscat
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009362:Neoplasm Metastasis; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology; D020005:Propanols / Q000494:pharmacology; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics*; D005466:Fluorocarbons
chemical_list: D001549:Benzamides; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010879:Piperazines; D020005:Propanols; D016212:Transforming Growth Factor beta; C575715:1,1,1,3,3,3-hexafluoro-2-(2-fluoro-4'-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)-(1,1'-biphenyl)-4-yl)propan-2-ol; C539900:RORC protein, human; C559087:SR 1078; D005466:Fluorocarbons
keywords: Breast cancer; Carcinogenesis; DNA repair; EMT (epithelial–mesenchymal transition); MaSC (mammary stem cell); Metastasis; Nuclear receptor; RNA-seq; RORγ (RORC, RORgamma); Stemness; TGF-β (TGF-beta)