Conserved role of FOXC1 in TNBC is parallel to FOXA1 in ER+ breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Triple-negative breast cancer (TNBC) lacks ER, PR, and HER2 receptors, rendering standard therapies ineffective.
• FOXC1 is a transcription factor overexpressed in TNBC, promoting cancer growth, metastasis, and stem-cell-like properties.
• The precise molecular function of FOXC1 in TNBC remains unclear due to tumor heterogeneity.

Purpose of the Study:

• To elucidate the molecular function and regulation of FOXC1 in TNBC.
• To identify FOXC1 cofactors and conserved regulatory targets.
• To explore therapeutic vulnerabilities associated with FOXC1 in different breast cancer subtypes.

Main Methods:

• Analysis of FOXC1 function across diverse TNBC cell lines.
• Identification of conserved FOXC1 binding sites (peaks) using ChIP-seq.
• Co-immunoprecipitation and functional assays to identify FOXC1 cofactors.
• Comparison of FOXC1 target gene regulation in TNBC and ER+ breast cancer.

Main Results:

• FOXC1 regulates key oncogenes and tumor suppressors in TNBC, with varied functional impact across cell lines.
• Differential responses to CDK4/6 inhibitors were observed upon FOXC1 loss, indicating functional heterogeneity.
• A conserved set of FOXC1 binding sites was identified across TNBC cell lines.
• The nuclear receptor NR2F2 was identified as a cofactor for FOXC1.
• Core FOXC1 targets in TNBC are regulated similarly by FOXA1 and NR2F2 in ER+ breast cancer.

Conclusions:

• FOXC1 plays a critical role in TNBC, but its function is heterogeneous.
• NR2F2 is a druggable cofactor of FOXC1, presenting a potential therapeutic target.
• Understanding FOXC1 regulation by FOXA1 and NR2F2 offers insights into parallel regulatory mechanisms in different breast cancer subtypes.