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FOXM1 transcriptionally regulates expression of integrin β1 in triple-negative breast cancer
Zuhal Hamurcu1,2,3, Nermin Kahraman1, Ahmed Ashour1
1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX, 77030, USA.
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 β1 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 β1 (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 β1 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 β1 gene and drives its expression.
Results:
We demonstrated that FOXM1 directly binds to the promoter of integrin β1 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 β1 gene expression and that FOXM1/ Integrin-β1/FAK axis may play an important role in the progression of TNBC.
Insights
Forkhead box M1 (FOXM1) directly regulates Integrin beta 1 (ITGB1) gene expression in triple-negative breast cancer. This FOXM1/ITGB1/FAK pathway is crucial for TNBC progression.
Area of Science:
- Oncology
- Molecular Biology
- Gene Regulation
Background:
- Triple-negative breast cancer (TNBC) is aggressive, characterized by metastasis and poor survival.
- Forkhead box M1 (FOXM1) is overexpressed in TNBC and plays an oncogenic role.
- Integrin beta 1 (ITGB1) is upregulated in invasive breast cancers, correlating with poor outcomes.
Purpose of the Study:
- To elucidate the molecular mechanisms by which FOXM1 drives oncogenic effects in TNBC.
- To investigate the regulation of Integrin beta 1 (ITGB1) gene expression in TNBC.
- To explore the role of the FOXM1 transcription factor in TNBC progression.
Main Methods:
- Utilized normal breast epithelial (MCF10A) and TNBC cell lines (MDA-MB-231, BT-20, MDA-MB436).
- Employed siRNA-based knockdown to inhibit ITGB1 expression, confirmed by RT-PCR and Western blot.
- Used Chromatin Immunoprecipitation (ChIP) and luciferase reporter assays to confirm FOXM1 binding to the ITGB1 promoter.
Main Results:
- Demonstrated direct binding of FOXM1 to the ITGB1 gene promoter.
- Showed that FOXM1 transcriptionally regulates ITGB1 expression in TNBC cells.
- Confirmed FOXM1's regulation of Integrin beta 1 and focal adhesion kinase (FAK) activity.
Conclusions:
- FOXM1 directly regulates Integrin beta 1 gene expression.
- The FOXM1/Integrin-β1/FAK axis is implicated in the progression of triple-negative breast cancer.
- FOXM1 represents a potential therapeutic target for TNBC.