Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Int J Cancer. 2012 Jan 1;130(1):71-82. doi: 10.1002/ijc.25977. Epub 2011 Apr 20.
BEX2 is a member of brain expressed X-linked gene family that is differentially expressed in primary breast tumors. We have previously demonstrated that BEX2 expression protects breast cancer cells against mitochondrial apoptosis and G1 cell cycle arrest. In addition, we have shown that BEX2 is a c-Jun target gene and, in turn, regulates the phosphorylation of c-Jun in breast cancer cells. In our study, we investigated BEX2 protein expression in a tissue microarray cohort of 225 breast tissue samples with known clinical, pathological and biomarker information. We observed that BEX2 protein was overexpressed in ∼50% of malignant breast tumors compared to only 7% of benign breast samples. Notably, BEX2 positive tumors identified a subset of breast cancers with the overexpression of ErbB2 and phosphorylated c-Jun proteins. Furthermore, using in vitro models, we demonstrated that the mechanism of this association is a functional feedback loop involving ErbB2, c-Jun and BEX2 in breast cancer cells. In this feedback loop, ErbB2 overexpression results in an induction of c-Jun and BEX2 expression. Importantly, ErbB2 induction of BEX2 expression was abrogated by a dominant-negative mutant of c-Jun, suggesting that this effect was mediated through the regulation of c-Jun signaling. In turn, the overexpression of BEX2 led to an increase in both c-Jun-mediated induction of ErbB2 and c-Jun binding to the ErbB2 promoter in MCF-7 cells. Our study suggests that BEX2 protein is overexpressed in approximately half of breast cancers and has a positive feedback loop with ErbB2 mediated by c-Jun signaling in breast cancer cells.
BEX2 是脑表达的 X 连锁基因家族的成员，在原发性乳腺癌中差异表达。我们之前已经证明，BEX2 表达可保护乳腺癌细胞免受线粒体凋亡和 G1 细胞周期阻滞。此外，我们已经表明，BEX2 是 c-Jun 的靶基因，并且反过来调节乳腺癌细胞中 c-Jun 的磷酸化。在我们的研究中，我们在包含已知临床、病理和生物标志物信息的 225 例乳腺组织样本的组织微阵列队列中研究了 BEX2 蛋白的表达。我们观察到，与仅 7%的良性乳腺样本相比，BEX2 蛋白在约 50%的恶性乳腺肿瘤中过表达。值得注意的是，BEX2 阳性肿瘤鉴定出了一组乳腺癌，这些乳腺癌的 ErbB2 和磷酸化 c-Jun 蛋白过表达。此外，我们使用体外模型证明了这种关联的机制是涉及乳腺癌细胞中的 ErbB2、c-Jun 和 BEX2 的功能反馈回路。在这个反馈回路中，ErbB2 过表达导致 c-Jun 和 BEX2 的表达诱导。重要的是，c-Jun 显性失活突变体可阻断 ErbB2 诱导的 BEX2 表达，这表明这种效应是通过 c-Jun 信号转导的调节介导的。反过来，BEX2 的过表达导致 MCF-7 细胞中 c-Jun 介导的 ErbB2 诱导和 c-Jun 与 ErbB2 启动子结合均增加。我们的研究表明，BEX2 蛋白在大约一半的乳腺癌中过表达，并通过乳腺癌细胞中的 c-Jun 信号转导与 ErbB2 形成正反馈回路。
