Journal
CELL REPORTS
Volume 13, Issue 5, Pages 1046-1058Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.09.063
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Funding
- NIH [CA151610]
- Avon Foundation [02-2014-063]
- David Salomon Translational Breast Cancer Research Fund
- Fashion Footwear Charitable Foundation of New York, Inc.
- Margie and Robert E. Petersen Foundation
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The mesoderm-and epithelial-mesenchymal transition-associated transcription factor FOXC1 is specifically overexpressed in basal-like breast cancer (BLBC), but its biochemical function is not understood. Here, we demonstrate that FOXC1 controls cancer stem cell (CSC) properties enriched in BLBC cells via activation of Smoothened (SMO)-independent Hedgehog (Hh) signaling. This non-canonical activation of Hh is specifically mediated by Gli2. Furthermore, we show that the N-terminal domain of FOXC1 (aa 1-68) binds directly to an internal region (aa 898-1168) of Gli2, enhancing the DNA-binding and transcription-activating capacity of Gli2. FOXC1 expression correlates with that of Gli2 and its targets in human breast cancers. Moreover, FOXC1 over-expression reduces sensitivity to anti-Hedgehog (Hh) inhibitors in BLBC cells and xenograft tumors. Together, these findings reveal FOXC1-mediated non-canonical Hh signaling that determines the BLBC stem-like phenotype and anti-Hh sensitivity, supporting inhibition of FOXC1 pathways as potential approaches for improving BLBC treatment.
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