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

doi:10.1016/j.celrep.2015.09.063

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
pp. 1046 – 1058

Abstract

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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 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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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