The S100A7-c-Jun activation domain binding protein 1 pathway enhances prosurvival pathways in breast cancer
The S100A7-c-Jun activation domain binding protein 1 pathway enhances prosurvival pathways in breast cancer
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DOI：
10.1158/0008-5472.can-04-3927
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发表时间：
2005-07-01
期刊：
影响因子：
11.2
通讯作者：
Watson, PH
中科院分区：
文献类型：
--
作者：
Emberley, ED;Niu, YL;Watson, PH
S100A7是侵袭前乳腺癌中表达最多的基因之一，在侵袭性疾病中表达时是生存不良的标志，并在实验模型中促进乳腺肿瘤进展。为了探索其作用机制，我们检测了S100A7在细胞存活中的作用，发现在MDA-MB-231细胞系中，过表达S100A7可促进非锚定生长条件下的存活。这种作用与核因子- κ B（3倍）和磷酸化- akt（4倍）的活性增加相平行，这两个已知介导促生存途径。S100A7和phospho-Akt在免疫组化检测的乳腺肿瘤中也存在相关性（n = 142, P < 0.0001, r = 0.34）。为了探索潜在的机制，我们使用一组MDA-MB-231乳腺细胞系，稳定转染了在jab1结构域突变的S100A7或S100A7，研究了假定的c-jun激活结构域结合蛋白I （jab1）结合结构域在S100A7中的作用。通过三维蛋白建模、免疫沉淀和酵母双杂交实验的结构分析以及转染报告基因和Western blot的功能分析表明，S100A7对磷酸化- akt和核因子- κ B通路的体外作用依赖于jab - 1结合位点和与jab1的相互作用。表皮生长因子受体信号的增强也与磷酸化akt的增加相关。此外，jab1结合结构域也是S100A7在小鼠体内异种移植肿瘤中表达增强致瘤性所必需的。我们得出的结论是，S100A7-jab1通路在细胞应激条件下（如anoikis）提高存活，这可能促进乳腺癌的进展。
S100A7 is among the most highly expressed genes in preinvasive breast cancer, is a marker of poor survival when expressed in invasive disease, and promotes breast tumor progression in experimental models. To explore the mechanism of action, we examined the role of S100A7 in cell survival and found that overexpression of S100A7 in MDA-MB-231 cell lines promotes survival under conditions of anchorage-independent growth. This effect is paralleled by increased activity of nuclear factor-kappa B (3-fold) and phospho-Akt (4-fold), which are known to mediate prosurvival pathways. S100A7 and phospho-Akt are also correlated in breast tumors examined by immunohistochemistry (n = 142; P < 0.0001; r = 0.34). To explore the underlying mechanism, we examined the role of a putative c-jun activation domain-binding protein I (jab1)-binding domain within S100A7 using a panel of MDA-MB-231 breast cell lines stably transfected with either S100A7 or S100A7 mutated at the jab1 domain. Structural analysis by three-dimensional protein modeling, immunoprecipitation, and yeast two-hybrid assay and functional analysis using transfected reporter gene and Western blot assays revealed that the in vitro effects of S100A7 on phospho-Akt and the nuclear factor-kappa B pathway are dependent on the jab I -binding site and the interaction with jab1. Enhanced epidermal growth factor receptor signaling was also found to correlate with the increased phospho-Akt. Furthermore, the jab1-binding domain is also necessary for the enhanced tumorigenicity conferred by S100A7 expression in murine xenograft tumors in vivo. We conclude that the S100A7-jab1 pathway acts to enhance survival under conditions of cellular stress, such as anoikis, which may promote progression of breast cancer.