Department of Pathology, Barbara Ann Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Breast Cancer Res Treat. 2010 Jul;122(2):337-46. doi: 10.1007/s10549-009-0572-1. Epub 2009 Oct 8.
Forkhead box M1 (FoxM1) transcription factor is known to play important role in human cancers which, in part, is mediated by its ability to modulate cell cycle regulatory proteins as well as genes involved in cell proliferation and differentiation. In breast cancer, FoxM1 down-regulation is increasingly being recognized as an important mechanism for the targeted activity of anti-cancer agents. However, the mechanistic insight in support of the role of FoxM1 in aggressive breast cancer is poorly understood. We have tested the biological consequence of FoxM1 down-regulation and up-regulation in breast cancer cell lines and found that the down-regulation of FoxM1 in MDA-MB-231 and SUM149 cells by siRNA approach inhibited cell growth, clonogenicity, migration, and invasion. We also found decreased expression of CDK2 and E2F1 with concomitant increase in p21 and p27 proteins, suggesting an important role of FoxM1 in cell cycle progression. In contrast, over-expression of FoxM1 by cDNA transfection, in breast cancer cells (SUM102 and SKBR3) expressing low levels of FoxM1, resulted in increased cell proliferation, migration, and invasion. Moreover, down-regulation of FoxM1 inhibited the expression of many factors that are involved in the degradation of extra cellular matrix and angiogenesis such as uPA, uPAR, MMP-2, MMP-9, and vascular endothelial growth factor (VEGF) as well as inhibited the activity of MMP-9 and VEGF. Interestingly, over-expression of uPA by cDNA transfection abrogated the cellular effects that were observed by the down-regulation of FoxM1. Taken together, these results suggest the potential application of FoxM1 down-regulation as a novel approach for the treatment of aggressive breast cancer.
叉头框转录因子 M1（FoxM1）已知在人类癌症中发挥重要作用，部分原因是其能够调节细胞周期调节蛋白以及参与细胞增殖和分化的基因。在乳腺癌中，FoxM1 的下调越来越被认为是抗癌药物靶向活性的重要机制。然而，支持 FoxM1 在侵袭性乳腺癌中作用的机制见解理解甚少。我们已经测试了乳腺癌细胞系中 FoxM1 下调和上调的生物学后果，发现通过 siRNA 方法下调 MDA-MB-231 和 SUM149 细胞中的 FoxM1 抑制了细胞生长、集落形成、迁移和侵袭。我们还发现 CDK2 和 E2F1 的表达减少，同时 p21 和 p27 蛋白增加，表明 FoxM1 在细胞周期进程中起着重要作用。相比之下，通过 cDNA 转染在表达低水平 FoxM1 的乳腺癌细胞（SUM102 和 SKBR3）中过表达 FoxM1，导致细胞增殖、迁移和侵袭增加。此外，下调 FoxM1 抑制了许多参与细胞外基质降解和血管生成的因子的表达，如 uPA、uPAR、MMP-2、MMP-9 和血管内皮生长因子（VEGF），并抑制了 MMP-9 和 VEGF 的活性。有趣的是，通过 cDNA 转染过表达 uPA 可消除由 FoxM1 下调观察到的细胞效应。总之，这些结果表明下调 FoxM1 作为治疗侵袭性乳腺癌的新方法具有潜在的应用价值。
