Negative Regulation of NF-κB by the ING4 Tumor Suppressor in Breast Cancer
| Autor: | Elizabeth Min, Tanya S. Thal, Suwon Kim, Coya Tapia, Aprill Watanabe, David O. Azorsa, Galen Hostetter, Tanya H. Little, Sara A. Byron |
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| Rok vydání: | 2012 |
| Předmět: |
Transcription
Genetic Gene Expression Cell Cycle Proteins 0302 clinical medicine Molecular Cell Biology Breast Tumors Gene expression Signaling in Cellular Processes Phosphorylation 0303 health sciences Multidisciplinary Tissue microarray Obstetrics and Gynecology Antibodies Monoclonal Genomics 3. Good health Oncology 030220 oncology & carcinogenesis Disease Progression Tetradecanoylphorbol Acetate Medicine Antibody Research Article Signal Transduction Science Down-Regulation CA 15-3 Breast Neoplasms Biology Disease-Free Survival 03 medical and health sciences Breast cancer Cell Line Tumor Breast Cancer Genetics Cancer Genetics medicine Humans Neoplasm Invasiveness 030304 developmental biology Homeodomain Proteins Tumor Suppressor Proteins Transcription Factor RelA Cancers and Neoplasms Gene signature medicine.disease Tumor progression Immunology Cancer research biology.protein Ectopic expression Transcriptional Signaling Gene Function Genome Expression Analysis |
| Zdroj: | PLoS ONE, Vol 7, Iss 10, p e46823 (2012) PLoS ONE Byron, Sara A; Min, Elizabeth; Thal, Tanya S; Hostetter, Galen; Watanabe, Aprill T; Azorsa, David O; Little, Tanya H; Tapia, Coya; Kim, Suwon (2012). Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer. PLoS ONE, 7(10), e46823. Lawrence, Kans.: Public Library of Science 10.1371/journal.pone.0046823 |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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