2. Academic Validation
  3. FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer

FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer

  • Cell Rep. 2015 Nov 3;13(5):1046-58. doi: 10.1016/j.celrep.2015.09.063.
Bingchen Han 1,  Ying Qu 1,  Yanli Jin 1,  Yi Yu 1,  Nan Deng 2,  Kolja Wawrowsky 3,  Xiao Zhang 2,  Na Li 4,  Shikha Bose 5,  Qiang Wang 6,  Sugunadevi Sakkiah 7,  Ravinder Abrol 7,  Tor W Jensen 8,  Benjamin P Berman 6,  Hisashi Tanaka 1,  Jeffrey Johnson 1,  Bowen Gao 1,  Jijun Hao 9,  Zhenqiu Liu 2,  Ralph Buttyan 10,  Partha S Ray 8,  Mien-Chie Hung 11,  Armando E Giuliano 1,  Xiaojiang Cui 12
Affiliations

Affiliations

  • 1 Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 2 Biostatistics and Bioinformatics Research Center, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 3 Department of BioMedical Sciences, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 4 Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
  • 5 Department of Pathology, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 6 Department of Medicine, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 7 Department of BioMedical Sciences, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Medicine, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 8 Department of Surgery, University of Illinois College of Medicine at Urbana Champaign, Urbana, IL 61801, USA.
  • 9 College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, USA.
  • 10 Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
  • 11 Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 402, Taiwan.
  • 12 Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Obstetrics and Gynecology, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: xiaojiang.cui@cshs.org.
PMID: 26565916 DOI: 10.1016/j.celrep.2015.09.063
Abstract

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 overexpression 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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