FOXM1 transcriptionally regulates expression of integrin ß1 in triple-negative breast cancer.

ABSTRACT

PURPOSE: 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 ß1 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 ß1 (ITGB1) gene expression have not been well elucidated. METHODS: 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 ß1 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 ß1 gene and drives its expression. RESULTS: We demonstrated that FOXM1 directly binds to the promoter of integrin ß1 gene and transcriptionally regulates its expression and activity of focal adhesion kinase (FAK) in TNBC cells. CONCLUSION: Our study suggests that FOXM1 transcription factor regulates Integrin ß1 gene expression and that FOXM1/ Integrin-ß1/FAK axis may play an important role in the progression of TNBC.