CCAAT/Enhancer binding protein delta (c/EBPdelta) regulation and expression in human mammary epithelial cells: I. "Loss of function" alterations in the c/EBPdelta growth inhibitory pathway in breast cancer cell lines.
CCAAT/Enhancer binding protein delta (c/EBPdelta) regulation and expression in human mammary epithelial cells: I. "Loss of function" alterations in the c/EBPdelta growth inhibitory pathway in breast cancer cell lines.
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DOI：
10.1002/jcb.20223
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发表时间：
2004-11
影响因子：
4
通讯作者：
G. S. Sivko;J. Dewille
中科院分区：
文献类型：
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作者：
G. S. Sivko;J. Dewille
生长抑制信号转导途径中的“功能丧失”改变在癌细胞中是常见的。在这项研究中，我们表明生长停滞（GA）治疗-血清和生长因子的撤出和生长抑制IL-6家族细胞因子，（白细胞介素-6和抑瘤素M（OSM））-增加STAT 3磷酸化（pSTAT 3），增加CCAAT增强子结合蛋白δ（C/EBP δ）基因表达并诱导原代有限寿命的人乳腺上皮细胞（HMEC）的GA，和永生化乳腺细胞系（MCF-10A和MCF-12 A）。相反，从人乳腺癌细胞系（MCF-7、SK-BR-3、T-47 D和MDA-MB-231）中去除血清和生长因子长达48小时诱导pSTAT 3水平和C/EBP δ基因表达的相对适度增加，并导致不同水平的GA。在大多数乳腺癌细胞系中，IL-6家族细胞因子处理增加了pSTAT 3水平和C/EBP delta基因表达，然而，生长抑制是细胞系依赖性的。除了生长抑制途径中的“功能丧失”改变之外，乳腺癌细胞系还表现出生长信号传导途径中的“功能获得”改变。Akt生长/存活途径在T-47 D和MCF-7乳腺癌细胞中被组成性激活。Akt抑制剂LY 294，002通过血清和生长因子去除或IL-6家族细胞因子处理显著增强T-47 D生长抑制。最后，我们发现pSTAT 3/C/EBP δ生长控制通路的激活与雌激素受体状态无关。这些结果表明，pSTAT 3/C/EBP δ生长抑制信号转导途径中的“功能丧失”改变在人乳腺癌细胞系中相对常见。pSTAT 3/ C/EBP δ生长抑制信号转导通路的缺陷性激活，连同Akt生长刺激通路的组成性激活，可能在乳腺癌的病因学或进展中发挥协同作用。
"Loss of function" alterations in growth inhibitory signal transduction pathways are common in cancer cells. In this study, we show that growth arrest (GA) treatments--serum and growth factor withdrawal and growth inhibitory IL-6 family cytokines (Interleukin-6 and Oncostatin M (OSM))--increase STAT3 phosphorylation (pSTAT3), increase CCAAT enhancer binding protein delta (C/EBPdelta) gene expression and induce GA of primary, finite-lifespan human mammary epithelial cells (HMECs), and immortalized breast cell lines (MCF-10A and MCF-12A). In contrast, serum and growth factor withdrawal from human breast cancer cell lines (MCF-7, SK-BR-3, T-47D, and MDA-MB-231) for up to 48 h induced a relatively modest increase in pSTAT3 levels and C/EBPdelta gene expression and resulted in varying levels of GA. In most breast cancer cell lines, IL-6 family cytokine treatment increased pSTAT3 levels and C/EBPdelta gene expression, however, growth inhibition was cell line dependent. In addition to "loss of function" alterations in growth inhibitory pathways, breast cancer cell lines also exhibit "gain of function" alterations in growth signaling pathways. The Akt growth/ survival pathway is constitutively activated in T-47D and MCF-7 breast cancer cells. The Akt inhibitor LY 294,002 significantly enhanced T-47D growth inhibition by serum and growth factor withdrawal or IL-6 family cytokine treatment. Finally, we show that activation of the pSTAT3/C/EBPdelta growth control pathway is independent of estrogen receptor status. These results demonstrate that "loss of function" alterations in the pSTAT3/C/EBPdelta growth inhibitory signal transduction pathway are relatively common in human breast cancer cell lines. Defective activation of the pSTAT3/ C/EBPdelta growth inhibitory signal transduction pathway, in conjunction with constitutive activation of the Akt growth stimulatory pathway, may play a synergistic role in the etiology or progression of breast cancer.