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TMPRSS2- Driven ERG Expression In Vivo Increases Self-Renewal and Maintains Expression in a Castration Resistant Subpopulation

Genomic rearrangements commonly occur in many types of cancers and often initiate or alter the progression of disease. Here we describe an in vivo mouse model that recapitulates the most frequent rearrangement in prostate cancer, the fusion of the promoter region of TMPRSS2 with the coding region of...

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Autores principales: Casey, Orla M., Fang, Lei, Hynes, Paul G., Abou-Kheir, Wassim G., Martin, Philip L., Tillman, Heather S., Petrovics, Gyorgy, Awwad, Hibah O., Ward, Yvona, Lake, Ross, Zhang, Luhua, Kelly, Kathleen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408501/
https://www.ncbi.nlm.nih.gov/pubmed/22860005
http://dx.doi.org/10.1371/journal.pone.0041668
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author Casey, Orla M.
Fang, Lei
Hynes, Paul G.
Abou-Kheir, Wassim G.
Martin, Philip L.
Tillman, Heather S.
Petrovics, Gyorgy
Awwad, Hibah O.
Ward, Yvona
Lake, Ross
Zhang, Luhua
Kelly, Kathleen
author_facet Casey, Orla M.
Fang, Lei
Hynes, Paul G.
Abou-Kheir, Wassim G.
Martin, Philip L.
Tillman, Heather S.
Petrovics, Gyorgy
Awwad, Hibah O.
Ward, Yvona
Lake, Ross
Zhang, Luhua
Kelly, Kathleen
author_sort Casey, Orla M.
collection PubMed
description Genomic rearrangements commonly occur in many types of cancers and often initiate or alter the progression of disease. Here we describe an in vivo mouse model that recapitulates the most frequent rearrangement in prostate cancer, the fusion of the promoter region of TMPRSS2 with the coding region of the transcription factor, ERG. A recombinant bacterial artificial chromosome including an extended TMPRSS2 promoter driving genomic ERG was constructed and used for transgenesis in mice. TMPRSS2-ERG expression was evaluated in tissue sections and FACS-fractionated prostate cell populations. In addition to the anticipated expression in luminal cells, TMPRSS2-ERG was similarly expressed in the Sca-1(hi)/EpCAM(+) basal/progenitor fraction, where expanded numbers of clonogenic self-renewing progenitors were found, as assayed by in vitro sphere formation. These clonogenic cells increased intrinsic self renewal in subsequent generations. In addition, ERG dependent self-renewal and invasion in vitro was demonstrated in prostate cell lines derived from the model. Clinical studies have suggested that the TMPRSS2-ERG translocation occurs early in prostate cancer development. In the model described here, the presence of the TMPRSS2-ERG fusion alone was not transforming but synergized with heterozygous Pten deletion to promote PIN. Taken together, these data suggest that one function of TMPRSS2-ERG is the expansion of self-renewing cells, which may serve as targets for subsequent mutations. Primary prostate epithelial cells demonstrated increased post transcriptional turnover of ERG compared to the TMPRSS2-ERG positive VCaP cell line, originally isolated from a prostate cancer metastasis. Finally, we determined that TMPRSS2-ERG expression occurred in both castration-sensitive and resistant prostate epithelial subpopulations, suggesting the existence of androgen-independent mechanisms of TMPRSS2 expression in prostate epithelium.
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spelling pubmed-34085012012-08-02 TMPRSS2- Driven ERG Expression In Vivo Increases Self-Renewal and Maintains Expression in a Castration Resistant Subpopulation Casey, Orla M. Fang, Lei Hynes, Paul G. Abou-Kheir, Wassim G. Martin, Philip L. Tillman, Heather S. Petrovics, Gyorgy Awwad, Hibah O. Ward, Yvona Lake, Ross Zhang, Luhua Kelly, Kathleen PLoS One Research Article Genomic rearrangements commonly occur in many types of cancers and often initiate or alter the progression of disease. Here we describe an in vivo mouse model that recapitulates the most frequent rearrangement in prostate cancer, the fusion of the promoter region of TMPRSS2 with the coding region of the transcription factor, ERG. A recombinant bacterial artificial chromosome including an extended TMPRSS2 promoter driving genomic ERG was constructed and used for transgenesis in mice. TMPRSS2-ERG expression was evaluated in tissue sections and FACS-fractionated prostate cell populations. In addition to the anticipated expression in luminal cells, TMPRSS2-ERG was similarly expressed in the Sca-1(hi)/EpCAM(+) basal/progenitor fraction, where expanded numbers of clonogenic self-renewing progenitors were found, as assayed by in vitro sphere formation. These clonogenic cells increased intrinsic self renewal in subsequent generations. In addition, ERG dependent self-renewal and invasion in vitro was demonstrated in prostate cell lines derived from the model. Clinical studies have suggested that the TMPRSS2-ERG translocation occurs early in prostate cancer development. In the model described here, the presence of the TMPRSS2-ERG fusion alone was not transforming but synergized with heterozygous Pten deletion to promote PIN. Taken together, these data suggest that one function of TMPRSS2-ERG is the expansion of self-renewing cells, which may serve as targets for subsequent mutations. Primary prostate epithelial cells demonstrated increased post transcriptional turnover of ERG compared to the TMPRSS2-ERG positive VCaP cell line, originally isolated from a prostate cancer metastasis. Finally, we determined that TMPRSS2-ERG expression occurred in both castration-sensitive and resistant prostate epithelial subpopulations, suggesting the existence of androgen-independent mechanisms of TMPRSS2 expression in prostate epithelium. Public Library of Science 2012-07-30 /pmc/articles/PMC3408501/ /pubmed/22860005 http://dx.doi.org/10.1371/journal.pone.0041668 Text en © 2012 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Casey, Orla M.
Fang, Lei
Hynes, Paul G.
Abou-Kheir, Wassim G.
Martin, Philip L.
Tillman, Heather S.
Petrovics, Gyorgy
Awwad, Hibah O.
Ward, Yvona
Lake, Ross
Zhang, Luhua
Kelly, Kathleen
TMPRSS2- Driven ERG Expression In Vivo Increases Self-Renewal and Maintains Expression in a Castration Resistant Subpopulation
title TMPRSS2- Driven ERG Expression In Vivo Increases Self-Renewal and Maintains Expression in a Castration Resistant Subpopulation
title_full TMPRSS2- Driven ERG Expression In Vivo Increases Self-Renewal and Maintains Expression in a Castration Resistant Subpopulation
title_fullStr TMPRSS2- Driven ERG Expression In Vivo Increases Self-Renewal and Maintains Expression in a Castration Resistant Subpopulation
title_full_unstemmed TMPRSS2- Driven ERG Expression In Vivo Increases Self-Renewal and Maintains Expression in a Castration Resistant Subpopulation
title_short TMPRSS2- Driven ERG Expression In Vivo Increases Self-Renewal and Maintains Expression in a Castration Resistant Subpopulation
title_sort tmprss2- driven erg expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408501/
https://www.ncbi.nlm.nih.gov/pubmed/22860005
http://dx.doi.org/10.1371/journal.pone.0041668
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