NF-κB and Estrogen Receptor α Interactions: Differential Function in Estrogen Receptor-Negative and -Positive Hormone-independent Breast Cancer Cells
NF-κB and Estrogen Receptor α Interactions: Differential Function in Estrogen Receptor-Negative and -Positive Hormone-independent Breast Cancer Cells
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DOI：
10.1002/jcb.22141
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发表时间：
2009-06-01
影响因子：
4
通讯作者：
Pratt, M. A. Christine
中科院分区：
文献类型：
--
作者：
Gionet, Nathalie;Jansson, Deidre;Pratt, M. A. Christine
雌激素受体（ER）阳性乳腺癌细胞具有低水平的组成型NF-κ B活性，而ER阴性（-）细胞和非雌激素依赖性细胞具有相对高水平的组成型NF-κ B活性。在这项研究中，我们研究了ER α和NF-κ B蛋白在ER+和ER-β-依赖细胞中相互抑制的方面。ER α的异位表达减少了ER+和ER-乳腺癌细胞系中的细胞数量，而在ER-细胞中NF-κ B结合活性和几种NF-κ B调节蛋白的表达减少。ER+/E2非依赖性LCC 1细胞中的ER过表达仅微弱地抑制主要的p50 NF-κ B。GST-ER α融合蛋白唐斯和NF-κ B B：ER α复合物的体内免疫共沉淀显示ER α在体外和体内与p50和p65相互作用。抑制NF-κ B可增加多种E2调节蛋白的表达。在LCC 1和MCF-7细胞中，p50通过超位移分析直接与ER：ERE复合物差异相关，而p65抗体在没有超位移的情况下减少ER α：ERE复合物。ChIP分析表明NF-κ B蛋白存在于内源性ERE上。总之，这些结果表明，ER和NF-κ B经历相互抑制，这可以部分解释为什么ER-细胞中ER α的表达不赋予生长信号。其次，ER+细胞中E2非依赖性的获得主要与p50：p50 NF-κ B相关，这可能反映了这些细胞中ER的改变。由于p50同二聚体对ER的存在不太敏感，这可能允许在同一细胞中激活两种途径。J.细胞。107：448-459，2009. (C)2009威利-利斯公司
Estrogen receptor (ER)-positive breast cancer cells have low levels of constitutive NF-kappa B activity while ER negative (-) cells and hormone-independent cells have relatively high constitutive levels of NF-kappa B activity. In this study, we have examined the aspects of mutual repression between the ER alpha and NF-kappa B proteins in ER+ and ER- hormone-in dependent cells. Ectopic expression of the ERa reduced cell numbers in ER+ and ER- breast cancer cell lines while NF-kappa B-binding activity and the expression Of Several NF-kappa B-regulated proteins were reduced in ER- cells. ER overexpression in ER+/E2-independent LCC1 cells only weakly inhibited the predominant p50 NF-kappa B. GST-ER alpha fusion protein pull downs and in vivo co-immunoprecipitations of NF-kappa B:ER alpha complexes showed that the ER alpha interacts with p50 and p65 in vitro and in vivo. Inhibition of NF-kappa B increased the expression of diverse E2-regulated proteins. p50 differentially associated directly with the ER:ERE complex in LCC1 and MCF-7 cells by supershift analysis while p65 antibody reduced ER alpha:ERE complexes in the absence of a supershift. ChIP analysis demonstrated that NF-kappa B proteins are present on an endogenous ERE. Together these results demonstrate that the ER and NF-kappa B undergo mutual repression, which may explain, in part, why expression of the ER alpha in ER-cells does not confer growth signaling. Secondly, the acquisition of E2-independence in ER+ cells is associated with predominantly p50:p50 NF-kappa B, which may reflect alterations in the ER in these cells. Since the p50 homodimer is less sensitive to the presence of the ER, this may allow for the activation of both pathways in the same cell. J. Cell. Biochem. 107: 448-459, 2009. (C) 2009 Wiley-Liss, Inc.