FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance
FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance
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DOI：
10.1016/j.cellsig.2015.09.013
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发表时间：
2015-12-01
影响因子：
4.8
通讯作者：
Maia, Raquel C.
中科院分区：
文献类型：
--
作者：
de Moraes, Gabriela Nestal;Delbue, Deborah;Maia, Raquel C.
耐药性是成功治疗乳腺癌的主要障碍，乳腺癌是全世界妇女死亡的主要原因。FOXM1转录因子是一种有效的癌基因，在转录水平上调节一系列与DNA修复、转移、细胞侵袭和迁移有关的靶基因。然而，人们对FOXM1在细胞存活中的作用和涉及的基因靶点知之甚少。在这里，我们发现FOXM1过表达的乳腺癌细胞表现出抗凋亡的表型，这与XIAP和Survivin抗凋亡基因的表达上调有关。相反，FOXM1基因敲除导致XIAP和Survivin下调，并减少FOXM1与XIAP和Survivin启动子区域的结合。始终，FOXM1、XIAP和Survivin在紫杉烷和蒽环类耐药细胞系中的表达水平高于其敏感的相应细胞系，并且不能在药物治疗的反应中被直接调控。与我们的体外研究结果一致，我们发现FOXM1的表达与Survivin和XIAP在Illa期乳腺浸润性导管癌患者中的表达显著相关。重要的是，共表达FOXM1、Survivin和核XIAP的患者总体生存率显著降低，进一步证实了FOXM1调节Survivin和XIAP的生理学相关性。综上所述，这些发现表明FOXM1、XIAP和Survivin的过度表达有助于乳腺癌患者耐药的发展，并与不良的临床预后有关。(C)爱思唯尔公司出版的2015年。
Drug resistance is a major hurdle for successful treatment of breast cancer, the leading cause of deaths in women throughout the world. The FOXM1 transcription factor is a potent oncogene that transcriptionally regulates a wide range of target genes involved in DNA repair, metastasis, cell invasion, and migration. However, little is known about the role of FOXM1 in cell survival and the gene targets involved. Here, we show that FOXM1-overexpressing breast cancer cells display an apoptosis-resistant phenotype, which associates with the upregulation of expression of XIAP and Survivin antiapoptotic genes. Conversely, FOXM1 knockdown results in XIAP and Survivin downregulation as well as decreased binding of FOXM1 to the promoter regions of XIAP and Survivin. Consistently, FOXM1, XIAP, and Survivin expression levels were higher in taxane and anthracycline-resistant cell lines when compared to their sensitive counterparts and could not be dowhregulated in response to drug treatment. In agreement with our in vitro findings, we found that FOXM1 expression is significantly associated with Survivin and XIAP expression in samples from patients with Illa stage breast invasive ductal carcinoma. Importantly, patients co-expressing FOXM1, Survivin, and nuclear XIAP had significantly worst overall survival, further confirming the physiological relevance of the regulation of Survivin and XIAP by FOXM1. Together, these findings suggest that the overexpression of FOXM1, XIAP, and Survivin contributes to the development of drug-resistance and is associated with poor clinical outcome in breast cancer patients. (C) 2015 Published by Elsevier Inc.