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

ABSTRACT: Nuclear Factor kappa B (NF-?B) 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-?B 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-?B (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-?B-target gene expression in T47D cells, indicating that ING4 inhibited NF-?B activity in breast cancer cells. Supportive of the ING4 function in the regulation of NF-?B-target gene expression, we found that ING4 expression levels inversely correlated with the expression of NF-?B-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-?B-target genes was associated with reduced disease-free survival in breast cancer patients. Taken together, we conclude that ING4 negatively regulates NF-?B in breast cancer. Consequently, down-regulation of ING4 leads to activation of NF-?B, contributing to tumor progression and reduced disease-free patient survival in breast cancer.

SUBMITTER: Byron SA

PROVIDER: S-EPMC3464231 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

Byron Sara A SA Min Elizabeth E Thal Tanya S TS Hostetter Galen G Watanabe Aprill T AT Azorsa David O DO Little Tanya H TH Tapia Coya C Kim Suwon S

PloS one 20121004 10

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) ...[more]

PMID: 23056468

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Project description:BACKGROUND:Inhibitor of differentiation protein 4 (ID4) is a dominant negative regulator of the basic helix-loop-helix (bHLH) family of transcription factors. During tumorigenesis, ID4 may act as a tumor suppressor or as an oncogene in different tumor types. However, the role of ID4 in breast cancer is not clear where both an oncogenic and a tumor suppressor function have been attributed. Here, we hypothesize that ID4 behaves as both, but its role in breast differs according to the estrogen receptor (ER) status of the tumor. METHODS:ID4 expression was retrieved from TCGA database using UCSC Xena. Association between overall survival (OS) and ID4 was assessed using Kaplan-Meier plotter. Correlation between methylation and expression was analyzed using the MEXPRESS tool. In vitro experiments involved ectopic expression of ID4 in MCF-7, T47D, and MDA-MB231 breast cancer cell lines. Migration and colony formation capacity were assessed after transfection treatments. Gene expression was analyzed by ddPCR and methylation by MSP, MS-MLPA, or ddMSP. RESULTS:Data mining analysis revealed that ID4 expression is significantly lower in ER+ tumors with respect to ER- tumors or normal tissue. We also demonstrate that ID4 is significantly methylated in ER+ tumors. Kaplan-Meier analysis indicated that low ID4 expression levels were associated with poor overall survival in patients with ER+ tumors. In silico expression analysis indicated that ID4 was associated with the expression of key genes of the ER pathway only in ER+ tumors. In vitro experiments revealed that ID4 overexpression in ER+ cell lines resulted in decreased migration capacity and reduced number of colonies. ID4 overexpression induced a reduction in ER levels in ER+ cell lines, while estrogen deprivation with fulvestrant did not induce changes neither in ID4 methylation nor in ID4 expression. CONCLUSIONS:We propose that ID4 is frequently silenced by promoter methylation in ER+ breast cancers and functions as a tumor suppressor gene in these tumors, probably due to its interaction with key genes of the ER pathway. Our present study contributes to the knowledge of the role of ID4 in breast cancer.

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

Publications

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

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