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The role of FOXC1/FOXCUT/DANCR axis in triple negative breast cancer: a bioinformatics and experimental approach
Zeeba Kamaliyan1, Reza Mirfakhraie2,3, Ghasem Azizi-Tabesh1,4
1Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Koodakyar St, Velenjak Ave, Chamran Highway, 19395-4719, Tehran, Iran.
Background:
Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer and does not benefit from the existing targeted therapies. In the present study, we used bioinformatics and experimental approaches to assess the genes that are somehow involved in the epithelial-mesenchymal transition (EMT) pathway which may explain the invasive features of TNBC.
Method And Results:
We analyzed five GEO datasets consisting of 657 breast tumors by GEO2R online software to achieve common differentially expressed genes (DEGs) between TNBC and non-TNBC tumors. The expression of the selected coding and non-coding genes was validated in 100 breast tumors, including fifty TNBC and fifty non-TNBC samples, using quantitative Real-Time PCR (qRT-PCR). The bioinformatics approach resulted in a final DEG list consisting of ten upregulated and seventeen downregulated genes (logFC ≥|1| and P < 0.05). Co-expression network construction indicated the FOXC1 transcription factor as a central hub node. Considering the notable role of FOXC1 in EMT, the expression levels of FOXC1-related lncRNAs, lnc-FOXCUT and lnc-DANCR, were also evaluated in the studied tumors. The results of qRT-PCR confirmed notable upregulation of FOXC1, lnc-FOXCUT, and lnc-DANCR in TNBC tissues compared to non-TNBC samples (P < 0.0001, P = 0.0005, and P = 0.0008, respectively). Moreover, ROC curve analysis revealed the potential biomarker role of FOXC1 in TNBC samples.
Conclusion:
Present study suggested that the deregulation of FOXC1/lnc-FOXCUT/lnc-DANCR axis may contribute to the aggressive features of triple-negative breast tumors. Therefore, this axis may be considered as a new probable therapeutic target in the treatment of TNBC.
Insights
Triple-negative breast cancer (TNBC) is aggressive due to the FOXC1/lnc-FOXCUT/lnc-DANCR axis. This pathway's deregulation contributes to TNBC's invasive features, offering a potential new therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its aggressive nature and lack of targeted therapy options.
- The epithelial-mesenchymal transition (EMT) pathway is implicated in the invasive characteristics of TNBC, necessitating investigation into related genes.
- Understanding the molecular drivers of TNBC invasiveness is crucial for developing effective treatment strategies.
Purpose of the Study:
- To identify genes involved in the epithelial-mesenchymal transition (EMT) pathway that contribute to the aggressive phenotype of triple-negative breast cancer (TNBC).
- To investigate the role of the FOXC1 transcription factor and its associated long non-coding RNAs (lncRNAs), lnc-FOXCUT and lnc-DANCR, in TNBC.
- To evaluate the potential of the FOXC1/lnc-FOXCUT/lnc-DANCR axis as a therapeutic target for TNBC.
Main Methods:
- Analysis of five Gene Expression Omnibus (GEO) datasets comprising 657 breast tumors to identify common differentially expressed genes (DEGs) between TNBC and non-TNBC.
- Validation of selected gene expression using quantitative Real-Time PCR (qRT-PCR) in 100 breast tumor samples (50 TNBC, 50 non-TNBC).
- Construction of a co-expression network to identify key regulatory factors, followed by evaluation of FOXC1 and related lncRNAs (lnc-FOXCUT, lnc-DANCR).
Main Results:
- A list of 27 differentially expressed genes (10 upregulated, 17 downregulated) was identified between TNBC and non-TNBC.
- The transcription factor FOXC1 was identified as a central hub in the co-expression network and showed significant upregulation in TNBC.
- Quantitative Real-Time PCR confirmed the upregulation of FOXC1, lnc-FOXCUT, and lnc-DANCR in TNBC tissues, with ROC curve analysis indicating FOXC1's potential as a biomarker.
Conclusions:
- The deregulation of the FOXC1/lnc-FOXCUT/lnc-DANCR axis is suggested to contribute to the aggressive and invasive features observed in triple-negative breast tumors.
- This identified axis represents a promising novel therapeutic target for the treatment of triple-negative breast cancer.
- Further research into targeting this axis could lead to improved clinical outcomes for TNBC patients.
