FoxM1 down-regulation leads to inhibition of proliferation, migration and invasion of breast cancer cells through the modulation of extra-cellular matrix degrading factors (Retracted article. See vol. 158, pg. 607, 2016)
FoxM1 down-regulation leads to inhibition of proliferation, migration and invasion of breast cancer cells through the modulation of extra-cellular matrix degrading factors (Retracted article. See vol. 158, pg. 607, 2016)
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DOI：
10.1007/s10549-009-0572-1
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发表时间：
2010-07-01
影响因子：
3.8
通讯作者：
Sarkar, Fazlul H.
中科院分区：
文献类型：
--
作者：
Ahmad, Aamir;Wang, Zhiwei;Sarkar, Fazlul H.
叉头盒M1（FoxM 1）转录因子在人类癌症中起重要作用，其部分通过其调节细胞周期调节蛋白以及参与细胞增殖和分化的基因的能力来介导。在乳腺癌中，FoxM 1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FoxM 1在侵袭性乳腺癌中作用的机制见解知之甚少。我们已经测试了乳腺癌细胞系中FoxM 1下调和上调的生物学后果，发现通过siRNA方法下调MDA-MB-231和SUM 149细胞中的FoxM 1抑制细胞生长、克隆形成、迁移和侵袭。我们还发现CDK 2和E2 F1的表达减少，同时p21和p27蛋白的表达增加，表明FoxM 1在细胞周期进程中的重要作用。相反，在表达低水平FoxM 1的乳腺癌细胞（SUM 102和SKBR 3）中，通过cDNA转染过表达FoxM 1导致细胞增殖、迁移和侵袭增加。下调FoxM 1表达可抑制uPA、uPAR、MMP-2、MMP-9、VEGF等多种参与细胞外基质降解和血管生成的因子的表达，并抑制MMP-9和VEGF的活性。有趣的是，通过cDNA转染过度表达uPA消除了通过下调FoxM 1观察到的细胞效应。总之，这些结果表明FoxM 1下调作为治疗侵袭性乳腺癌的新方法的潜在应用。
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.