FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair
FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair
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DOI：
10.1093/carcin/bgs167
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发表时间：
2012-10-01
期刊：
影响因子：
4.7
通讯作者：
Lee, Ju-Seog
中科院分区：
文献类型：
--
作者：
Park, Yun-Yong;Jung, Sung Yun;Lee, Ju-Seog
转录因子是癌症中改变的信号通路的直接效应物，并且经常决定癌症患者的临床结果。为了发现决定乳腺癌临床结果的新转录因子，我们系统地分析了乳腺癌患者的基因表达数据。我们的研究结果表明，叉头盒蛋白M1（FOXM1）是三阴性乳腺癌患者中排名第一的生存相关转录因子。令人惊讶的是，沉默FOXM1表达导致乳腺癌细胞对阿霉素（Dox）变得更加敏感。我们发现，FOXM1依赖性耐药性Dox介导的调节DNA修复基因。我们进一步证明了NFB 1在Dox存在下与FOXM 1相互作用，以保护乳腺癌细胞免受DNA损伤。最后，在小鼠异种移植模型中，沉默乳腺癌细胞中的FOXM1表达显著地使细胞对Dox敏感。我们的系统方法通过调节DNA修复基因确定了FOXM1在Dox耐药性中的意想不到的作用，我们的研究结果为FOXM1如何介导对Dox的耐药性提供了机制见解，并证明FOXM1可能是一种有前途的治疗靶点，可使乳腺癌细胞对Dox敏感。
Transcription factors are direct effectors of altered signaling pathways in cancer and frequently determine clinical outcomes in cancer patients. To uncover new transcription factors that would determine clinical outcomes in breast cancer, we systematically analyzed gene expression data from breast cancer patients. Our results revealed that Forkhead box protein M1 (FOXM1) is the top-ranked survival-associated transcription factor in patients with triple-negative breast cancer. Surprisingly, silencing FOXM1 expression led breast cancer cells to become more sensitive to doxorubicin (Dox). We found that FOXM1-dependent resistance to Dox is mediated by regulating DNA repair genes. We further demonstrated that NFB1 interacts with FOXM1 in the presence of Dox to protect breast cancer cells from DNA damage. Finally, silencing FOXM1 expression in breast cancer cells in a mouse xenograft model significantly sensitized the cells to Dox. Our systematic approaches identified an unexpected role of FOXM1 in Dox resistance by regulating DNA repair genes, and our findings provide mechanistic insights into how FOXM1 mediates resistance to Dox and evidence that FOXM1 may be a promising therapeutic target for sensitizing breast cancer cells to Dox.