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EZH2 regulates expression of FOXC1 by mediating H3K27me3 in breast cancers
Xiang-Jin Zheng1,2, Wan Li1,2, Jie Yi3
1The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China.
Abstract:
Triple-negative breast cancer (TNBC) is characterized by low expression of human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER), and progesterone receptor (PR), which is the most aggressive subtype with poor outcome among breast cancers. The underlying mechanisms of TNBC remain unclear and there is a lack of biomarkers. In this study we conducted an in silico assay and found that FOXC1 was highly expressed in ER-/PR-/HER2- breast cancers, which was confirmed by qRT-PCR, immunohistochemistry, and Western blot analysis. FOXC1 was more highly expressed in TNBCs than the other breast cancers. Kaplan-Meier plotter revealed that expression of FOXC1 was associated with overall survival (OS) of patients with breast cancers. Expression of FOXC1 was reversely associated with level of H3K27me3, which was methylated by EZH2. In MCF-7 and T47D cells, inhibition of EZH2 by DZNeP or GSK343 concentration- and time-dependently increased expression of FOXC1. Finally, we demonstrated that the expression of FOXC1 was associated with resistance of doxorubicin treatment of breast cancer cells. In conclusion, these results suggest that FOXC1 may be a potential biomarker or drug target for TNBCs, and that downregulation of FOXC1 could have therapeutic value in treatment of TNBCs.
Insights
FOXC1 is highly expressed in triple-negative breast cancer (TNBC) and linked to poor survival and doxorubicin resistance. Targeting FOXC1 may offer new therapeutic strategies for TNBC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype lacking specific biomarkers and effective treatments.
- Understanding TNBC's underlying mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of FOXC1 in TNBC.
- To identify potential biomarkers and therapeutic targets for TNBC.
Main Methods:
- In silico analysis, qRT-PCR, immunohistochemistry, and Western blot were used to assess FOXC1 expression.
- Kaplan-Meier plotter analyzed the association between FOXC1 expression and patient survival.
- Cell-based assays examined the relationship between FOXC1, EZH2, H3K27me3, and doxorubicin resistance.
Main Results:
- FOXC1 was significantly upregulated in TNBC compared to other breast cancer subtypes.
- High FOXC1 expression correlated with poorer overall survival in breast cancer patients.
- FOXC1 expression was inversely associated with H3K27me3 levels, modulated by EZH2.
- FOXC1 expression was linked to doxorubicin resistance in breast cancer cells.
Conclusions:
- FOXC1 may serve as a potential biomarker for TNBC.
- Targeting FOXC1, possibly by downregulating its expression, could be a therapeutic strategy for TNBC.
- Further research into FOXC1's role could lead to novel treatments for this aggressive cancer subtype.
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