Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer.
Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer.
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DOI：
10.1371/journal.pone.0046823
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kim S
中科院分区：
文献类型：
--
作者：
Byron SA;Min E;Thal TS;Hostetter G;Watanabe AT;Azorsa DO;Little TH;Tapia C;Kim S
核因子κB （NF-κB）是正常免疫反应的关键介质，但当异常激活时，会导致侵袭性癌细胞表型。本研究表明，生长4抑制剂（ING4）肿瘤抑制因子在乳腺癌中负调控NF-κB。我们使用组织微阵列和新生成的抗体检测了原发乳腺肿瘤样本中ING4蛋白的表达。我们发现34%的肿瘤无法检测到低水平的ING4蛋白表达（n = 227）。ING4低表达的肿瘤通常体积大、分级高、淋巴结阳性，提示ING4的下调可能促进乳腺癌的进展。在相同的肿瘤组中，我们发现ING4的低表达与核磷酸化p65/RelA （p-p65）的高水平相关（p = 0.018）， p-p65是NF-κB的一种活化形式。57%的ing4低/p-p65高的肿瘤为淋巴结阳性，表明这些肿瘤具有高转移倾向。相反，ING4的异位表达抑制了T47D和MCF7乳腺癌细胞中p65/RelA的磷酸化。此外，ING4抑制pma诱导的细胞侵袭和T47D细胞中NF-κB靶基因的表达，表明ING4抑制乳腺癌细胞中NF-κB的活性。通过分析公开的基因表达数据，我们发现ING4在原发性乳腺肿瘤中的表达水平与NF-κ b靶基因的表达呈负相关，支持了ING4在调节NF-κ b靶基因表达中的功能。此外，ING4低表达或ING4抑制NF-κ b靶基因子集组成的基因特征高表达与乳腺癌患者无病生存率降低相关。综上所述，我们认为ING4在乳腺癌中负调控NF-κB。因此，ING4的下调导致NF-κB的激活，有助于乳腺癌的肿瘤进展和降低无病患者的生存率。
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.
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影响因子：
9.3
作者：
Hu Z;Fan C;Livasy C;He X;Oh DS;Ewend MG;Carey LA;Subramanian S;West R;Ikpatt F;Olopade OI;van de Rijn M;Perou CM
通讯作者：
Perou CM
DOI：
10.1186/bcr1678
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Howe LR
通讯作者：
Howe LR
DOI：
10.1073/pnas.0403621101
发表时间：
2004-07-06
影响因子：
11.1
作者：
Biswas, DK;Shi, Q;Iglehart, JD
通讯作者：
Iglehart, JD
DOI：
10.1073/pnas.0407158101
发表时间：
2004-11-16
影响因子：
11.1
作者：
Kim, S;Chin, K;Bishop, JM
通讯作者：
Bishop, JM
影响因子：
64.8
作者：
Garkavtsev, I;Kozin, SV;Jain, RK
通讯作者：
Jain, RK