Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation.
Prediction of therapeutic response and cancer patient survival can be improved by the identification of molecular markers including tumor Akt status. A direct correlation between NOS2 expression and elevated Akt phosphorylation status has been observed in breast tumors. Tissue inhibitor matrix metal...
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doaj-5a65063fd7054d7e9e1b11657caa0e772020-11-24T20:50:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0179e4408110.1371/journal.pone.0044081Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation.Lisa A RidnourKimberly M BaraschAlisha N WindhausenTiffany H DorseyMichael M LizardoHarris G YfantisDong H LeeChristopher H SwitzerRobert Y S ChengJulie L HeineckeErnst BrueggemannHarry B HinesChand KhannaSharon A GlynnStefan AmbsDavid A WinkPrediction of therapeutic response and cancer patient survival can be improved by the identification of molecular markers including tumor Akt status. A direct correlation between NOS2 expression and elevated Akt phosphorylation status has been observed in breast tumors. Tissue inhibitor matrix metalloproteinase-1 (TIMP-1) has been proposed to exert oncogenic properties through CD63 cell surface receptor pathway initiation of pro-survival PI3k/Akt signaling. We employed immunohistochemistry to examine the influence of TIMP-1 on the functional relationship between NOS2 and phosphorylated Akt in breast tumors and found that NOS2-associated Akt phosphorylation was significantly increased in tumors expressing high TIMP-1, indicating that TIMP-1 may further enhance NO-induced Akt pathway activation. Moreover, TIMP-1 silencing by antisense technology blocked NO-induced PI3k/Akt/BAD phosphorylation in cultured MDA-MB-231 human breast cancer cells. TIMP-1 protein nitration and TIMP-1/CD63 co-immunoprecipitation was observed at NO concentrations that induced PI3k/Akt/BAD pro-survival signaling. In the survival analysis, elevated tumor TIMP-1 predicted poor patient survival. This association appears to be mainly restricted to tumors with high NOS2 protein. In contrast, TIMP-1 did not predict poor survival in patient tumors with low NOS2 expression. In summary, our findings suggest that tumors with high TIMP-1 and NOS2 behave more aggressively by mechanisms that favor Akt pathway activation.http://europepmc.org/articles/PMC3434220?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lisa A Ridnour Kimberly M Barasch Alisha N Windhausen Tiffany H Dorsey Michael M Lizardo Harris G Yfantis Dong H Lee Christopher H Switzer Robert Y S Cheng Julie L Heinecke Ernst Brueggemann Harry B Hines Chand Khanna Sharon A Glynn Stefan Ambs David A Wink |
spellingShingle |
Lisa A Ridnour Kimberly M Barasch Alisha N Windhausen Tiffany H Dorsey Michael M Lizardo Harris G Yfantis Dong H Lee Christopher H Switzer Robert Y S Cheng Julie L Heinecke Ernst Brueggemann Harry B Hines Chand Khanna Sharon A Glynn Stefan Ambs David A Wink Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation. PLoS ONE |
author_facet |
Lisa A Ridnour Kimberly M Barasch Alisha N Windhausen Tiffany H Dorsey Michael M Lizardo Harris G Yfantis Dong H Lee Christopher H Switzer Robert Y S Cheng Julie L Heinecke Ernst Brueggemann Harry B Hines Chand Khanna Sharon A Glynn Stefan Ambs David A Wink |
author_sort |
Lisa A Ridnour |
title |
Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation. |
title_short |
Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation. |
title_full |
Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation. |
title_fullStr |
Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation. |
title_full_unstemmed |
Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation. |
title_sort |
nitric oxide synthase and breast cancer: role of timp-1 in no-mediated akt activation. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
Prediction of therapeutic response and cancer patient survival can be improved by the identification of molecular markers including tumor Akt status. A direct correlation between NOS2 expression and elevated Akt phosphorylation status has been observed in breast tumors. Tissue inhibitor matrix metalloproteinase-1 (TIMP-1) has been proposed to exert oncogenic properties through CD63 cell surface receptor pathway initiation of pro-survival PI3k/Akt signaling. We employed immunohistochemistry to examine the influence of TIMP-1 on the functional relationship between NOS2 and phosphorylated Akt in breast tumors and found that NOS2-associated Akt phosphorylation was significantly increased in tumors expressing high TIMP-1, indicating that TIMP-1 may further enhance NO-induced Akt pathway activation. Moreover, TIMP-1 silencing by antisense technology blocked NO-induced PI3k/Akt/BAD phosphorylation in cultured MDA-MB-231 human breast cancer cells. TIMP-1 protein nitration and TIMP-1/CD63 co-immunoprecipitation was observed at NO concentrations that induced PI3k/Akt/BAD pro-survival signaling. In the survival analysis, elevated tumor TIMP-1 predicted poor patient survival. This association appears to be mainly restricted to tumors with high NOS2 protein. In contrast, TIMP-1 did not predict poor survival in patient tumors with low NOS2 expression. In summary, our findings suggest that tumors with high TIMP-1 and NOS2 behave more aggressively by mechanisms that favor Akt pathway activation. |
url |
http://europepmc.org/articles/PMC3434220?pdf=render |
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