Montañez-Wiscovich M E, Seachrist D D, Landis M D, Visvader J, Andersen B, Keri R A
Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106-4965, USA.
Oncogene. 2009 Oct 15;28(41):3608-18. doi: 10.1038/onc.2009.221. Epub 2009 Aug 3.
ErbB2/HER2/Neu-overexpressing breast cancers are characterized by poor survival due to high proliferation and metastasis rates and identifying downstream targets of ErbB2 should facilitate developing novel therapies for this disease. Gene expression profiling revealed the transcriptional regulator LIM-only protein 4 (LMO4) is upregulated during ErbB2-induced mouse mammary gland tumorigenesis. Although LMO4 is frequently overexpressed in breast cancer and LMO4-overexpressing mice develop mammary epithelial tumors, the mechanisms involved are unknown. In this study, we report that LMO4 is a downstream target of ErbB2 and PI3K in ErbB2-dependent breast cancer cells. Furthermore, LMO4 silencing reduces proliferation of these cells, inducing a G2/M arrest that was associated with decreased cullin-3, an E3-ubiquitin ligase component important for mitosis. Loss of LMO4 subsequently results in reduced Cyclin D1 and Cyclin E. Further supporting a role for LMO4 in modulating proliferation by regulating cullin-3 expression, we found that LMO4 expression oscillates throughout the cell cycle with maximum expression occurring during G2/M and these changes precede oscillations in cullin-3 levels. LMO4 levels are also highest in high-grade/less differentiated breast cancers, which are characteristically highly proliferative. We conclude that LMO4 is a novel cell cycle regulator with a key role in mediating ErbB2-induced proliferation, a hallmark of ErbB2-positive disease.
表皮生长因子受体2（ErbB2）/人表皮生长因子受体2（HER2）/神经（Neu）过表达的乳腺癌具有高增殖率和转移率，其特征是生存率低。确定ErbB2的下游靶点应有助于开发针对这种疾病的新疗法。基因表达谱分析显示，在ErbB2诱导的小鼠乳腺肿瘤发生过程中，转录调节因子仅含LIM结构域蛋白4（LMO4）上调。尽管LMO4在乳腺癌中经常过表达，且过表达LMO4的小鼠会发生乳腺上皮肿瘤，但其涉及的机制尚不清楚。在本研究中，我们报告LMO4是ErbB2依赖性乳腺癌细胞中ErbB2和磷脂酰肌醇-3激酶（PI3K）的下游靶点。此外，LMO4沉默可降低这些细胞的增殖，诱导G2/M期阻滞，这与cullin-3的减少有关，cullin-3是一种对有丝分裂很重要的E3泛素连接酶成分。LMO4的缺失随后导致细胞周期蛋白D1和细胞周期蛋白E减少。进一步支持LMO4通过调节cullin-3表达来调节增殖的作用，我们发现LMO4的表达在整个细胞周期中振荡，在G2/M期表达最高，且这些变化先于cullin-3水平的振荡。LMO4水平在高级别/低分化乳腺癌中也最高，这些乳腺癌的特征是高度增殖。我们得出结论，LMO4是一种新型细胞周期调节因子，在介导ErbB2诱导的增殖中起关键作用，这是ErbB2阳性疾病的一个标志。
