FOXM1 transcriptionally regulates expression of integrin β1 in triple-negative breast cancer
FOXM1 transcriptionally regulates expression of integrin β1 in triple-negative breast cancer
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DOI：
10.1007/s10549-017-4207-7
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发表时间：
2017-06-01
影响因子：
3.8
通讯作者：
Ozpolat, Bulent
中科院分区：
文献类型：
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作者：
Hamurcu, Zuhal;Kahraman, Nermin;Ozpolat, Bulent
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌，与早期转移、耐药和患者生存率低有关。叉头盒M1 （FOXM1）被认为是一个新兴的分子靶点，因为它在85%的TNBC中具有致癌作用和高过表达。然而，FOXM1转录因子介导其致癌作用的分子机制尚不完全清楚。整合素β 1在浸润性乳腺癌中经常上调，并与TNBC中较差的临床结果和较短的总体患者生存期相关。然而，整合素β 1 （ITGB1）基因表达的调控机制尚未得到很好的阐明。正常乳腺上皮细胞（MCF10A）和TNBC细胞（即MDA-MB-231， BT-20 MDA-MB436）被用于研究。采用小干扰RNA （Small interfering RNA, siRNA）敲除抑制整合素β 1基因（Integrin β 1 gene, mRNA）和蛋白表达，分别采用RT-PCR和Western blot检测。利用染色质免疫沉淀（ChiP）和基因报告基因荧光素酶（Luciferase）检测证实FOXM1转录因子与整合素β 1基因启动子结合并驱动其表达。我们证明FOXM1直接结合整合素β 1基因的启动子，并转录调节TNBC细胞中其表达和局灶粘附激酶（FAK）的活性。本研究提示FOXM1转录因子调控整合素β 1基因表达，FOXM1/整合素β 1/FAK轴可能在TNBC的进展中发挥重要作用。
Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and associated with early metastasis, drug resistance, and poor patient survival. Fork head box M1 (FOXM1) is considered as an emerging molecular target due to its oncogenic role and high overexpression profile in 85% in TNBC. However, molecular mechanisms by which FOXM1 transcription factor mediate its oncogenic effects are not fully understood. Integrin beta 1 is often upregulated in invasive breast cancers and associated with poor clinical outcome and shorter overall patient survival in TNBC. However, the mechanisms regulating integrin beta 1 (ITGB1) gene expression have not been well elucidated.Normal breast epithelium (MCF10A) and TNBC cells (i.e., MDA-MB-231, BT-20 MDA-MB436) were used for the study. Small interfering RNA (siRNA)-based knockdown was used to inhibit Integrin beta 1 gene (mRNA) and protein expressions, which are detected by RT-PCR and Western blot, respectively. Chromatin immunoprecipitation (ChiP) and gene reporter (Luciferase) assays were used to demonstrate that FOXM1 transcription factor binds to the promoter of Integrin beta 1 gene and drives its expression.We demonstrated that FOXM1 directly binds to the promoter of integrin beta 1 gene and transcriptionally regulates its expression and activity of focal adhesion kinase (FAK) in TNBC cells.Our study suggests that FOXM1 transcription factor regulates Integrin beta 1 gene expression and that FOXM1/ Integrin-beta 1/FAK axis may play an important role in the progression of TNBC.