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A bi-stable feedback loop between GDNF, EGR1, and ERα contribute to endocrine resistant breast cancer
Discovering regulatory interactions between genes that specify the behavioral properties of cells remains an important challenge. We used the dynamics of transcriptional changes resolved by PRO-seq to identify a regulatory network responsible for endocrine resistance in breast cancer. We show that G...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882141/ https://www.ncbi.nlm.nih.gov/pubmed/29614078 http://dx.doi.org/10.1371/journal.pone.0194522 |
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author | Horibata, Sachi Rice, Edward J. Zheng, Hui Mukai, Chinatsu Chu, Tinyi Marks, Brooke A. Coonrod, Scott A. Danko, Charles G. |
author_facet | Horibata, Sachi Rice, Edward J. Zheng, Hui Mukai, Chinatsu Chu, Tinyi Marks, Brooke A. Coonrod, Scott A. Danko, Charles G. |
author_sort | Horibata, Sachi |
collection | PubMed |
description | Discovering regulatory interactions between genes that specify the behavioral properties of cells remains an important challenge. We used the dynamics of transcriptional changes resolved by PRO-seq to identify a regulatory network responsible for endocrine resistance in breast cancer. We show that GDNF leads to endocrine resistance by switching the active state in a bi-stable feedback loop between GDNF, EGR1, and the master transcription factor ERα. GDNF stimulates MAP kinase, activating the transcription factors SRF and AP-1. SRF initiates an immediate transcriptional response, activating EGR1 and suppressing ERα. Newly translated EGR1 protein activates endogenous GDNF, leading to constitutive GDNF and EGR1 up-regulation, and the sustained down-regulation of ERα. Endocrine resistant MCF-7 cells are constitutively in the GDNF-high/ ERα-low state, suggesting that the state in the bi-stable feedback loop may provide a ‘memory’ of endocrine resistance. Thus, we identified a regulatory network switch that contributes to drug resistance in breast cancer. |
format | Online Article Text |
id | pubmed-5882141 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-58821412018-04-13 A bi-stable feedback loop between GDNF, EGR1, and ERα contribute to endocrine resistant breast cancer Horibata, Sachi Rice, Edward J. Zheng, Hui Mukai, Chinatsu Chu, Tinyi Marks, Brooke A. Coonrod, Scott A. Danko, Charles G. PLoS One Research Article Discovering regulatory interactions between genes that specify the behavioral properties of cells remains an important challenge. We used the dynamics of transcriptional changes resolved by PRO-seq to identify a regulatory network responsible for endocrine resistance in breast cancer. We show that GDNF leads to endocrine resistance by switching the active state in a bi-stable feedback loop between GDNF, EGR1, and the master transcription factor ERα. GDNF stimulates MAP kinase, activating the transcription factors SRF and AP-1. SRF initiates an immediate transcriptional response, activating EGR1 and suppressing ERα. Newly translated EGR1 protein activates endogenous GDNF, leading to constitutive GDNF and EGR1 up-regulation, and the sustained down-regulation of ERα. Endocrine resistant MCF-7 cells are constitutively in the GDNF-high/ ERα-low state, suggesting that the state in the bi-stable feedback loop may provide a ‘memory’ of endocrine resistance. Thus, we identified a regulatory network switch that contributes to drug resistance in breast cancer. Public Library of Science 2018-04-03 /pmc/articles/PMC5882141/ /pubmed/29614078 http://dx.doi.org/10.1371/journal.pone.0194522 Text en © 2018 Horibata et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Horibata, Sachi Rice, Edward J. Zheng, Hui Mukai, Chinatsu Chu, Tinyi Marks, Brooke A. Coonrod, Scott A. Danko, Charles G. A bi-stable feedback loop between GDNF, EGR1, and ERα contribute to endocrine resistant breast cancer |
title | A bi-stable feedback loop between GDNF, EGR1, and ERα contribute to endocrine resistant breast cancer |
title_full | A bi-stable feedback loop between GDNF, EGR1, and ERα contribute to endocrine resistant breast cancer |
title_fullStr | A bi-stable feedback loop between GDNF, EGR1, and ERα contribute to endocrine resistant breast cancer |
title_full_unstemmed | A bi-stable feedback loop between GDNF, EGR1, and ERα contribute to endocrine resistant breast cancer |
title_short | A bi-stable feedback loop between GDNF, EGR1, and ERα contribute to endocrine resistant breast cancer |
title_sort | bi-stable feedback loop between gdnf, egr1, and erα contribute to endocrine resistant breast cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882141/ https://www.ncbi.nlm.nih.gov/pubmed/29614078 http://dx.doi.org/10.1371/journal.pone.0194522 |
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