Negative Regulation of NF-κB by the ING4 Tumor Suppressor in Breast Cancer

Sara A. Byron, Elizabeth Min, Tanya S. Thal, Galen Hostetter, Aprill T. Watanabe, David O. Azorsa, Tanya H. Little, Coya Tapia, Suwon Kim

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere46823
JournalPloS one
Volume7
Issue number10
DOIs
StatePublished - Oct 4 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Byron, S. A., Min, E., Thal, T. S., Hostetter, G., Watanabe, A. T., Azorsa, D. O., Little, T. H., Tapia, C., & Kim, S. (2012). Negative Regulation of NF-κB by the ING4 Tumor Suppressor in Breast Cancer. PloS one, 7(10), [e46823]. https://doi.org/10.1371/journal.pone.0046823