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

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 t...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856749/
https://www.ncbi.nlm.nih.gov/pubmed/27211549
http://dx.doi.org/10.1016/j.ebiom.2016.02.028
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author 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.
author_facet 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.
author_sort Oh, Tae Gyu
collection PubMed
description 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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spelling pubmed-48567492016-05-24 The Nuclear Receptor, RORγ, Regulates Pathways Necessary for Breast Cancer Metastasis 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. EBioMedicine Research Paper 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. Elsevier 2016-02-18 /pmc/articles/PMC4856749/ /pubmed/27211549 http://dx.doi.org/10.1016/j.ebiom.2016.02.028 Text en © 2016 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Research Paper
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.
The Nuclear Receptor, RORγ, Regulates Pathways Necessary for Breast Cancer Metastasis
title The Nuclear Receptor, RORγ, Regulates Pathways Necessary for Breast Cancer Metastasis
title_full The Nuclear Receptor, RORγ, Regulates Pathways Necessary for Breast Cancer Metastasis
title_fullStr The Nuclear Receptor, RORγ, Regulates Pathways Necessary for Breast Cancer Metastasis
title_full_unstemmed The Nuclear Receptor, RORγ, Regulates Pathways Necessary for Breast Cancer Metastasis
title_short The Nuclear Receptor, RORγ, Regulates Pathways Necessary for Breast Cancer Metastasis
title_sort nuclear receptor, rorγ, regulates pathways necessary for breast cancer metastasis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856749/
https://www.ncbi.nlm.nih.gov/pubmed/27211549
http://dx.doi.org/10.1016/j.ebiom.2016.02.028
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