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Determining PTEN Functional Status by Network Component Deduced Transcription Factor Activities

PTEN-controlled PI3K-AKT-mTOR pathway represents one of the most deregulated signaling pathways in human cancers. With many small molecule inhibitors that target PI3K-AKT-mTOR pathway being exploited clinically, sensitive and reliable ways of stratifying patients according to their PTEN functional s...

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Autores principales: Tran, Linh M., Chang, Chun-Ju, Plaisier, Seema, Wu, Shumin, Dang, Julie, Mischel, Paul S., Liao, James C., Graeber, Thomas G., Wu, Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275574/
https://www.ncbi.nlm.nih.gov/pubmed/22347425
http://dx.doi.org/10.1371/journal.pone.0031053
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author Tran, Linh M.
Chang, Chun-Ju
Plaisier, Seema
Wu, Shumin
Dang, Julie
Mischel, Paul S.
Liao, James C.
Graeber, Thomas G.
Wu, Hong
author_facet Tran, Linh M.
Chang, Chun-Ju
Plaisier, Seema
Wu, Shumin
Dang, Julie
Mischel, Paul S.
Liao, James C.
Graeber, Thomas G.
Wu, Hong
author_sort Tran, Linh M.
collection PubMed
description PTEN-controlled PI3K-AKT-mTOR pathway represents one of the most deregulated signaling pathways in human cancers. With many small molecule inhibitors that target PI3K-AKT-mTOR pathway being exploited clinically, sensitive and reliable ways of stratifying patients according to their PTEN functional status and determining treatment outcomes are urgently needed. Heterogeneous loss of PTEN is commonly associated with human cancers and yet PTEN can also be regulated on epigenetic, transcriptional or post-translational levels, which makes the use of simple protein or gene expression-based analyses in determining PTEN status less accurate. In this study, we used network component analysis to identify 20 transcription factors (TFs) whose activities deduced from their target gene expressions were immediately altered upon the re-expression of PTEN in a PTEN-inducible system. Interestingly, PTEN controls the activities (TFA) rather than the expression levels of majority of these TFs and these PTEN-controlled TFAs are substantially altered in prostate cancer mouse models. Importantly, the activities of these TFs can be used to predict PTEN status in human prostate, breast and brain tumor samples with enhanced reliability when compared to straightforward IHC-based or expression-based analysis. Furthermore, our analysis indicates that unique sets of PTEN-controlled TFAs significantly contribute to specific tumor types. Together, our findings reveal that TFAs may be used as “signatures” for predicting PTEN functional status and elucidate the transcriptional architectures underlying human cancers caused by PTEN loss.
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spelling pubmed-32755742012-02-15 Determining PTEN Functional Status by Network Component Deduced Transcription Factor Activities Tran, Linh M. Chang, Chun-Ju Plaisier, Seema Wu, Shumin Dang, Julie Mischel, Paul S. Liao, James C. Graeber, Thomas G. Wu, Hong PLoS One Research Article PTEN-controlled PI3K-AKT-mTOR pathway represents one of the most deregulated signaling pathways in human cancers. With many small molecule inhibitors that target PI3K-AKT-mTOR pathway being exploited clinically, sensitive and reliable ways of stratifying patients according to their PTEN functional status and determining treatment outcomes are urgently needed. Heterogeneous loss of PTEN is commonly associated with human cancers and yet PTEN can also be regulated on epigenetic, transcriptional or post-translational levels, which makes the use of simple protein or gene expression-based analyses in determining PTEN status less accurate. In this study, we used network component analysis to identify 20 transcription factors (TFs) whose activities deduced from their target gene expressions were immediately altered upon the re-expression of PTEN in a PTEN-inducible system. Interestingly, PTEN controls the activities (TFA) rather than the expression levels of majority of these TFs and these PTEN-controlled TFAs are substantially altered in prostate cancer mouse models. Importantly, the activities of these TFs can be used to predict PTEN status in human prostate, breast and brain tumor samples with enhanced reliability when compared to straightforward IHC-based or expression-based analysis. Furthermore, our analysis indicates that unique sets of PTEN-controlled TFAs significantly contribute to specific tumor types. Together, our findings reveal that TFAs may be used as “signatures” for predicting PTEN functional status and elucidate the transcriptional architectures underlying human cancers caused by PTEN loss. Public Library of Science 2012-02-08 /pmc/articles/PMC3275574/ /pubmed/22347425 http://dx.doi.org/10.1371/journal.pone.0031053 Text en Tran 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tran, Linh M.
Chang, Chun-Ju
Plaisier, Seema
Wu, Shumin
Dang, Julie
Mischel, Paul S.
Liao, James C.
Graeber, Thomas G.
Wu, Hong
Determining PTEN Functional Status by Network Component Deduced Transcription Factor Activities
title Determining PTEN Functional Status by Network Component Deduced Transcription Factor Activities
title_full Determining PTEN Functional Status by Network Component Deduced Transcription Factor Activities
title_fullStr Determining PTEN Functional Status by Network Component Deduced Transcription Factor Activities
title_full_unstemmed Determining PTEN Functional Status by Network Component Deduced Transcription Factor Activities
title_short Determining PTEN Functional Status by Network Component Deduced Transcription Factor Activities
title_sort determining pten functional status by network component deduced transcription factor activities
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275574/
https://www.ncbi.nlm.nih.gov/pubmed/22347425
http://dx.doi.org/10.1371/journal.pone.0031053
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