EBP1, an ErbB3-binding protein, is decreased in prostate cancer and implicated in hormone resistance.
EBP1, an ErbB3-binding protein, is decreased in prostate cancer and implicated in hormone resistance.
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DOI：
10.1158/1535-7163.mct-08-0526
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发表时间：
2008-10
影响因子：
5.7
通讯作者：
Hamburger AW
中科院分区：
文献类型：
--
作者：
Zhang Y;Linn D;Liu Z;Melamed J;Tavora F;Young CY;Burger AM;Hamburger AW
ErbB 2/ErbB 3异源二聚体异常激活雄激素受体（AR）有助于前列腺癌中激素抵抗的发展。EBP 1是一种ErbB 3结合蛋白，充当AR辅抑制子。由于EBP 1在难治性前列腺癌的临床前模型中减少，我们研究了EBP 1在人前列腺癌中的表达。我们发现，EBP 1基因的表达显着降低，前列腺癌组织相比，良性前列腺在mRNA和蛋白质水平。EBP 1表达的恢复在乳腺癌难治性LNCaP C81细胞系导致改善雄激素非依赖性表型的基础上建立的生物学标准和减少的一组AR靶基因的表达。ErbB 3配体调蛋白（HRG）刺激肿瘤难治性前列腺癌细胞生长和AKT磷酸化的能力被消除。EBP 1表达的短发夹状RNA的废除依赖性LNCaP细胞，经历细胞凋亡响应HRG，导致HRG刺激的细胞生长。EBP 1表达的恢复降低了雌性小鼠C81异种移植物的致瘤性，而EBP 1表达的消除增强了LNCaP细胞在雌性小鼠中生长的能力。我们的数据支持EBP 1通过抑制AR和HRG刺激的生长在激素难治性前列腺癌的发展中的作用，并提出了一种治疗雄激素难治性前列腺癌的新策略。
Aberrant activation of the androgen receptor (AR) by the ErbB2/ErbB3 heterodimer contributes to the development of hormone resistance in prostate cancer. EBP1, an ErbB3-binding protein, acts as an AR corepressor. As EBP1 is decreased in preclinical models of hormone-refractory prostate cancer, we studied the expression of EBP1 in human prostate cancer. We found that the expression of the EBP1 gene was significantly decreased in prostate cancer tissues compared with benign prostate at both mRNA and protein levels. Restoration of EBP1 expression in the hormone-refractory LNCaP C81 cell line led to an amelioration of the androgen-independent phenotype based on established biological criteria and a reduction in the expression of a cohort of AR target genes. The ability of the ErbB3 ligand heregulin (HRG) to stimulate growth and AKT phosphorylation of hormone-refractory prostate cancer cells was abolished. Abrogation of EBP1 expression by short hairpin RNA in hormone-dependent LNCaP cells, which undergo apoptosis in response to HRG, resulted in HRG-stimulated cell growth. Restoration of EBP1 expression decreased the tumorigenicity of C81 xenografts in female mice, whereas elimination of EBP1 expression enhanced the ability of LNCaP cells to grow in female mice. Our data support a role for EBP1 in the development of hormone-refractory prostate cancer via inhibition of both AR- and HRG-stimulated growth and present a novel strategy for treating androgen-refractory prostate cancer.