Cell Reports
(Nov 2015)
FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer
Bingchen Han,
Ying Qu,
Yanli Jin,
Yi Yu,
Nan Deng,
Kolja Wawrowsky,
Xiao Zhang,
Na Li,
Shikha Bose,
Qiang Wang,
Sugunadevi Sakkiah,
Ravinder Abrol,
Tor W. Jensen,
Benjamin P. Berman,
Hisashi Tanaka,
Jeffrey Johnson,
Bowen Gao,
Jijun Hao,
Zhenqiu Liu,
Ralph Buttyan,
Partha S. Ray,
Mien-Chie Hung,
Armando E. Giuliano,
Xiaojiang Cui
Affiliations
Bingchen Han
Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Ying Qu
Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Yanli Jin
Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Yi Yu
Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Nan Deng
Biostatistics and Bioinformatics Research Center, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Kolja Wawrowsky
Department of BioMedical Sciences, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Xiao Zhang
Biostatistics and Bioinformatics Research Center, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Na Li
Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
Shikha Bose
Department of Pathology, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Qiang Wang
Department of Medicine, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Sugunadevi Sakkiah
Department of BioMedical Sciences, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Ravinder Abrol
Department of BioMedical Sciences, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Tor W. Jensen
Department of Surgery, University of Illinois College of Medicine at Urbana Champaign, Urbana, IL 61801, USA
Benjamin P. Berman
Department of Medicine, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Hisashi Tanaka
Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Jeffrey Johnson
Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Bowen Gao
Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Jijun Hao
College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, USA
Zhenqiu Liu
Biostatistics and Bioinformatics Research Center, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Ralph Buttyan
Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
Partha S. Ray
Department of Surgery, University of Illinois College of Medicine at Urbana Champaign, Urbana, IL 61801, USA
Mien-Chie Hung
Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Armando E. Giuliano
Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Xiaojiang Cui
Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
DOI
https://doi.org/10.1016/j.celrep.2015.09.063
Journal volume & issue
Vol. 13,
no. 5
Abstract
Read online
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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