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ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer

The mechanisms underlying ETS-driven prostate cancer initiation and progression remain poorly understood due to a lack of model systems that recapitulate this phenotype. We generated a genetically engineered mouse with prostate-specific expression of the ETS factor, ETV4, at lower and higher protein...

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Autores principales: Li, Dan, Zhan, Yu, Wang, Naitao, Tang, Fanying, Lee, Cindy J., Bayshtok, Gabriella, Moore, Amanda R., Wong, Elissa W. P., Pachai, Mohini R., Xie, Yuanyuan, Sher, Jessica, Zhao, Jimmy L., Khudoynazarova, Makhzuna, Gopalan, Anuradha, Chan, Joseph, Khurana, Ekta, Shepherd, Peter, Navone, Nora M., Chi, Ping, Chen, Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10075989/
https://www.ncbi.nlm.nih.gov/pubmed/37018402
http://dx.doi.org/10.1126/sciadv.adc9446
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author Li, Dan
Zhan, Yu
Wang, Naitao
Tang, Fanying
Lee, Cindy J.
Bayshtok, Gabriella
Moore, Amanda R.
Wong, Elissa W. P.
Pachai, Mohini R.
Xie, Yuanyuan
Sher, Jessica
Zhao, Jimmy L.
Khudoynazarova, Makhzuna
Gopalan, Anuradha
Chan, Joseph
Khurana, Ekta
Shepherd, Peter
Navone, Nora M.
Chi, Ping
Chen, Yu
author_facet Li, Dan
Zhan, Yu
Wang, Naitao
Tang, Fanying
Lee, Cindy J.
Bayshtok, Gabriella
Moore, Amanda R.
Wong, Elissa W. P.
Pachai, Mohini R.
Xie, Yuanyuan
Sher, Jessica
Zhao, Jimmy L.
Khudoynazarova, Makhzuna
Gopalan, Anuradha
Chan, Joseph
Khurana, Ekta
Shepherd, Peter
Navone, Nora M.
Chi, Ping
Chen, Yu
author_sort Li, Dan
collection PubMed
description The mechanisms underlying ETS-driven prostate cancer initiation and progression remain poorly understood due to a lack of model systems that recapitulate this phenotype. We generated a genetically engineered mouse with prostate-specific expression of the ETS factor, ETV4, at lower and higher protein dosage through mutation of its degron. Lower-level expression of ETV4 caused mild luminal cell expansion without histologic abnormalities, and higher-level expression of stabilized ETV4 caused prostatic intraepithelial neoplasia (mPIN) with 100% penetrance within 1 week. Tumor progression was limited by p53-mediated senescence and Trp53 deletion cooperated with stabilized ETV4. The neoplastic cells expressed differentiation markers such as Nkx3.1 recapitulating luminal gene expression features of untreated human prostate cancer. Single-cell and bulk RNA sequencing showed that stabilized ETV4 induced a previously unidentified luminal-derived expression cluster with signatures of cell cycle, senescence, and epithelial-to-mesenchymal transition. These data suggest that ETS overexpression alone, at sufficient dosage, can initiate prostate neoplasia.
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spelling pubmed-100759892023-04-06 ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer Li, Dan Zhan, Yu Wang, Naitao Tang, Fanying Lee, Cindy J. Bayshtok, Gabriella Moore, Amanda R. Wong, Elissa W. P. Pachai, Mohini R. Xie, Yuanyuan Sher, Jessica Zhao, Jimmy L. Khudoynazarova, Makhzuna Gopalan, Anuradha Chan, Joseph Khurana, Ekta Shepherd, Peter Navone, Nora M. Chi, Ping Chen, Yu Sci Adv Biomedicine and Life Sciences The mechanisms underlying ETS-driven prostate cancer initiation and progression remain poorly understood due to a lack of model systems that recapitulate this phenotype. We generated a genetically engineered mouse with prostate-specific expression of the ETS factor, ETV4, at lower and higher protein dosage through mutation of its degron. Lower-level expression of ETV4 caused mild luminal cell expansion without histologic abnormalities, and higher-level expression of stabilized ETV4 caused prostatic intraepithelial neoplasia (mPIN) with 100% penetrance within 1 week. Tumor progression was limited by p53-mediated senescence and Trp53 deletion cooperated with stabilized ETV4. The neoplastic cells expressed differentiation markers such as Nkx3.1 recapitulating luminal gene expression features of untreated human prostate cancer. Single-cell and bulk RNA sequencing showed that stabilized ETV4 induced a previously unidentified luminal-derived expression cluster with signatures of cell cycle, senescence, and epithelial-to-mesenchymal transition. These data suggest that ETS overexpression alone, at sufficient dosage, can initiate prostate neoplasia. American Association for the Advancement of Science 2023-04-05 /pmc/articles/PMC10075989/ /pubmed/37018402 http://dx.doi.org/10.1126/sciadv.adc9446 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Li, Dan
Zhan, Yu
Wang, Naitao
Tang, Fanying
Lee, Cindy J.
Bayshtok, Gabriella
Moore, Amanda R.
Wong, Elissa W. P.
Pachai, Mohini R.
Xie, Yuanyuan
Sher, Jessica
Zhao, Jimmy L.
Khudoynazarova, Makhzuna
Gopalan, Anuradha
Chan, Joseph
Khurana, Ekta
Shepherd, Peter
Navone, Nora M.
Chi, Ping
Chen, Yu
ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer
title ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer
title_full ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer
title_fullStr ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer
title_full_unstemmed ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer
title_short ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer
title_sort etv4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10075989/
https://www.ncbi.nlm.nih.gov/pubmed/37018402
http://dx.doi.org/10.1126/sciadv.adc9446
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