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Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling

Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk betw...

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Autores principales: Singhal, Hari, Greene, Marianne E., Zarnke, Allison L., Laine, Muriel, Al Abosy, Rose, Chang, Ya-Fang, Dembo, Anna G., Schoenfelt, Kelly, Vadhi, Raga, Qiu, Xintao, Rao, Prakash, Santhamma, Bindu, Nair, Hareesh B., Nickisch, Klaus J., Long, Henry W., Becker, Lev, Brown, Myles, Greene, Geoffrey L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796974/
https://www.ncbi.nlm.nih.gov/pubmed/29435103
http://dx.doi.org/10.18632/oncotarget.21378
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author Singhal, Hari
Greene, Marianne E.
Zarnke, Allison L.
Laine, Muriel
Al Abosy, Rose
Chang, Ya-Fang
Dembo, Anna G.
Schoenfelt, Kelly
Vadhi, Raga
Qiu, Xintao
Rao, Prakash
Santhamma, Bindu
Nair, Hareesh B.
Nickisch, Klaus J.
Long, Henry W.
Becker, Lev
Brown, Myles
Greene, Geoffrey L.
author_facet Singhal, Hari
Greene, Marianne E.
Zarnke, Allison L.
Laine, Muriel
Al Abosy, Rose
Chang, Ya-Fang
Dembo, Anna G.
Schoenfelt, Kelly
Vadhi, Raga
Qiu, Xintao
Rao, Prakash
Santhamma, Bindu
Nair, Hareesh B.
Nickisch, Klaus J.
Long, Henry W.
Becker, Lev
Brown, Myles
Greene, Geoffrey L.
author_sort Singhal, Hari
collection PubMed
description Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic.
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spelling pubmed-57969742018-02-12 Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling Singhal, Hari Greene, Marianne E. Zarnke, Allison L. Laine, Muriel Al Abosy, Rose Chang, Ya-Fang Dembo, Anna G. Schoenfelt, Kelly Vadhi, Raga Qiu, Xintao Rao, Prakash Santhamma, Bindu Nair, Hareesh B. Nickisch, Klaus J. Long, Henry W. Becker, Lev Brown, Myles Greene, Geoffrey L. Oncotarget Priority Research Paper Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic. Impact Journals LLC 2017-09-28 /pmc/articles/PMC5796974/ /pubmed/29435103 http://dx.doi.org/10.18632/oncotarget.21378 Text en Copyright: © 2018 Singhal et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Priority Research Paper
Singhal, Hari
Greene, Marianne E.
Zarnke, Allison L.
Laine, Muriel
Al Abosy, Rose
Chang, Ya-Fang
Dembo, Anna G.
Schoenfelt, Kelly
Vadhi, Raga
Qiu, Xintao
Rao, Prakash
Santhamma, Bindu
Nair, Hareesh B.
Nickisch, Klaus J.
Long, Henry W.
Becker, Lev
Brown, Myles
Greene, Geoffrey L.
Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling
title Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling
title_full Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling
title_fullStr Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling
title_full_unstemmed Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling
title_short Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling
title_sort progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling
topic Priority Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796974/
https://www.ncbi.nlm.nih.gov/pubmed/29435103
http://dx.doi.org/10.18632/oncotarget.21378
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