EZH2 regulates expression of FOXC1 by mediating H3K27me3 in breast cancers

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.

Automated summary

This study identified high expression of FOXC1 in TNBC, which was associated with overall survival (OS) of patients and inversely correlated with H3K27me3 levels. Inhibition of EZH2 increased FOXC1 expression, which was also linked to doxorubicin resistance in breast cancer cells. This suggests that FOXC1 may serve as a potential biomarker or drug target for TNBCs, and downregulation of FOXC1 could be therapeutically valuable in TNBC treatment.