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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.
Highlights
Nuclear Factor kappa B (NF-kB) is a central molecule that mediates immune response by activating gene transcription
The results showed that patients with Inhibitor of Growth 4 (ING4)-low tumors had more than three times the rate of recurrence and significantly reduced disease-free survival (Figure 5B, Hazard Ratio (HR) = 3.22, 95% CI 1.24–5.63, log-rank P = 0.012), demonstrating that low ING4 expression was associated with reduced disease-free survival in estrogen receptor (ER)+ breast cancer
The results showed that high 14-ING4/NF-kB gene scores were significantly associated with reduced disease-free survival (HR = 2.23, 95% CI 1.031–4.57, p = 0.0413, Figure 5D), indicating that the high expression of ING4/NF-kB-target genes recapitulated the association between low ING4 expression and reduced disease-free survival
Summary
Nuclear Factor kappa B (NF-kB) is a central molecule that mediates immune response by activating gene transcription. The canonical pathway of NF-kB activation involves receptor signaling leading to phosphorylation and proteasome-mediated degradation of Inhibitor of kappa B (IkB), resulting in the release of the NF-kB subunits from the cytoplasmic IkB complex. The NF-kB subunits, p65/RelA and p50/NF-kB1, translocate into the nucleus where the p65/p50 heterodimers bind to target gene promoter sequences and activate transcription of a large number of genes including pro-inflammatory cytokines and chemokines, initiating the immune response [1,2]. NF-kB is constitutively active, resulting in elevated expression of NF-kB-target genes that elicit aggressive tumor cell behaviors including enhanced proliferation, survival, migration, invasion, metastasis, and therapy resistance [4,5]. The molecular alterations that lead to constitutive activation of NF-kB pose a vital problem relating to cancer etiology and therapy
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