Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer.

Nuclear Factor kappa B (NF-κB) is a key mediator of normal immune response but contributes to aggressive cancer cell phenotypes when aberrantly activated. Here we present evidence that the Inhibitor of Growth 4 (ING4) tumor suppressor negatively regulates NF-κB in breast cancer. We surveyed primary...

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Autores principales:	Sara A Byron, Elizabeth Min, Tanya S Thal, Galen Hostetter, Aprill T Watanabe, David O Azorsa, Tanya H Little, Coya Tapia, Suwon Kim
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7d675166899b403d8971cfe903ed08a5
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spelling	oai:doaj.org-article:7d675166899b403d8971cfe903ed08a52021-11-18T08:13:11ZNegative regulation of NF-κB by the ING4 tumor suppressor in breast cancer.1932-620310.1371/journal.pone.0046823https://doaj.org/article/7d675166899b403d8971cfe903ed08a52012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23056468/?tool=EBIhttps://doaj.org/toc/1932-6203Nuclear Factor kappa B (NF-κB) is a key mediator of normal immune response but contributes to aggressive cancer cell phenotypes when aberrantly activated. Here we present evidence that the Inhibitor of Growth 4 (ING4) tumor suppressor negatively regulates NF-κB in breast cancer. We surveyed primary breast tumor samples for ING4 protein expression using tissue microarrays and a newly generated antibody. We found that 34% of tumors expressed undetectable to low levels of the ING4 protein (n = 227). Tumors with low ING4 expression were frequently large in size, high grade, and lymph node positive, suggesting that down-regulation of ING4 may contribute to breast cancer progression. In the same tumor set, we found that low ING4 expression correlated with high levels of nuclear phosphorylated p65/RelA (p-p65), an activated form of NF-κB (p = 0.018). Fifty seven percent of ING4-low/p-p65-high tumors were lymph node-positive, indicating a high metastatic tendency of these tumors. Conversely, ectopic expression of ING4 inhibited p65/RelA phosphorylation in T47D and MCF7 breast cancer cells. In addition, ING4 suppressed PMA-induced cell invasion and NF-κB-target gene expression in T47D cells, indicating that ING4 inhibited NF-κB activity in breast cancer cells. Supportive of the ING4 function in the regulation of NF-κB-target gene expression, we found that ING4 expression levels inversely correlated with the expression of NF-κB-target genes in primary breast tumors by analyzing public gene expression datasets. Moreover, low ING4 expression or high expression of the gene signature composed of a subset of ING4-repressed NF-κB-target genes was associated with reduced disease-free survival in breast cancer patients. Taken together, we conclude that ING4 negatively regulates NF-κB in breast cancer. Consequently, down-regulation of ING4 leads to activation of NF-κB, contributing to tumor progression and reduced disease-free patient survival in breast cancer.Sara A ByronElizabeth MinTanya S ThalGalen HostetterAprill T WatanabeDavid O AzorsaTanya H LittleCoya TapiaSuwon KimPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 10, p e46823 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sara A Byron Elizabeth Min Tanya S Thal Galen Hostetter Aprill T Watanabe David O Azorsa Tanya H Little Coya Tapia Suwon Kim Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer.
description	Nuclear Factor kappa B (NF-κB) is a key mediator of normal immune response but contributes to aggressive cancer cell phenotypes when aberrantly activated. Here we present evidence that the Inhibitor of Growth 4 (ING4) tumor suppressor negatively regulates NF-κB in breast cancer. We surveyed primary breast tumor samples for ING4 protein expression using tissue microarrays and a newly generated antibody. We found that 34% of tumors expressed undetectable to low levels of the ING4 protein (n = 227). Tumors with low ING4 expression were frequently large in size, high grade, and lymph node positive, suggesting that down-regulation of ING4 may contribute to breast cancer progression. In the same tumor set, we found that low ING4 expression correlated with high levels of nuclear phosphorylated p65/RelA (p-p65), an activated form of NF-κB (p = 0.018). Fifty seven percent of ING4-low/p-p65-high tumors were lymph node-positive, indicating a high metastatic tendency of these tumors. Conversely, ectopic expression of ING4 inhibited p65/RelA phosphorylation in T47D and MCF7 breast cancer cells. In addition, ING4 suppressed PMA-induced cell invasion and NF-κB-target gene expression in T47D cells, indicating that ING4 inhibited NF-κB activity in breast cancer cells. Supportive of the ING4 function in the regulation of NF-κB-target gene expression, we found that ING4 expression levels inversely correlated with the expression of NF-κB-target genes in primary breast tumors by analyzing public gene expression datasets. Moreover, low ING4 expression or high expression of the gene signature composed of a subset of ING4-repressed NF-κB-target genes was associated with reduced disease-free survival in breast cancer patients. Taken together, we conclude that ING4 negatively regulates NF-κB in breast cancer. Consequently, down-regulation of ING4 leads to activation of NF-κB, contributing to tumor progression and reduced disease-free patient survival in breast cancer.
format	article
author	Sara A Byron Elizabeth Min Tanya S Thal Galen Hostetter Aprill T Watanabe David O Azorsa Tanya H Little Coya Tapia Suwon Kim
author_facet	Sara A Byron Elizabeth Min Tanya S Thal Galen Hostetter Aprill T Watanabe David O Azorsa Tanya H Little Coya Tapia Suwon Kim
author_sort	Sara A Byron
title	Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer.
title_short	Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer.
title_full	Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer.
title_fullStr	Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer.
title_full_unstemmed	Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer.
title_sort	negative regulation of nf-κb by the ing4 tumor suppressor in breast cancer.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/7d675166899b403d8971cfe903ed08a5
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Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer.

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