Conserved role of FOXC1 in TNBC is parallel to FOXA1 in ER+ breast cancer
Revathy Ramachandran,
Shakhzada Ibragimova,
Laura M. Woods,
Tamader AlHouqani,
Roshna Lawrence Gomez,
Fabrizio Simeoni,
Mahmood Y. Hachim,
Tim C.P. Somervaille,
Anna Philpott,
Jason S. Carroll,
Fahad R. Ali
Affiliations
Revathy Ramachandran
College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
Shakhzada Ibragimova
College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
Laura M. Woods
Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
Tamader AlHouqani
College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
Roshna Lawrence Gomez
College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
Fabrizio Simeoni
Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
Mahmood Y. Hachim
College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
Tim C.P. Somervaille
Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
Anna Philpott
Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK; Department of Oncology, University of Cambridge, Cambridge, UK
Jason S. Carroll
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
Fahad R. Ali
College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates; Corresponding author
Summary: Triple-negative breast cancer (TNBC) is characterized by lack of the estrogen (ER) receptor, progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), and standard receptor-targeted therapies are ineffective. FOXC1, a transcription factor aberrantly overexpressed in many cancers, drives growth, metastasis, and stem-cell-like properties in TNBC. However, the molecular function of FOXC1 is unknown, partly due to heterogeneity of TNBC. Here, we show that although FOXC1 regulates many cancer hallmarks in TNBC, its function is varied in different cell lines, highlighted by the differential response to CDK4/6 inhibitors upon FOXC1 loss. Despite this functional heterogeneity, we show that FOXC1 regulates key oncogenes and tumor suppressors and identify a set of core FOXC1 peaks conserved across TNBC cell lines. We identify the ER-associated and drug-targetable nuclear receptor NR2F2 as a cofactor of FOXC1. Finally, we show that core FOXC1 targets in TNBC are regulated in parallel by the pioneer factor FOXA1 and the nuclear receptor NR2F2 in ER + breast cancer.