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

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.

Authors

Bingchen Han¹, Ying Qu¹, Yanli Jin¹, Yi Yu¹, Nan Deng², Kolja Wawrowsky³, Xiao Zhang², Na Li⁴, Shikha Bose⁵, Qiang Wang⁶, Sugunadevi Sakkiah⁷, Ravinder Abrol⁷, Tor W Jensen⁸, Benjamin P Berman⁶, Hisashi Tanaka¹, Jeffrey Johnson¹, Bowen Gao¹, Jijun Hao⁹, Zhenqiu Liu², Ralph Buttyan¹⁰, Partha S Ray⁸, Mien-Chie Hung¹¹, Armando E Giuliano¹, Xiaojiang Cui¹²

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Line, Tumor
Female
Forkhead Transcription Factors / chemistry
Forkhead Transcription Factors / metabolism*
Gene Expression Regulation, Neoplastic*
HEK293 Cells
Humans
Kruppel-Like Transcription Factors / chemistry
Kruppel-Like Transcription Factors / metabolism*
Nuclear Proteins / chemistry
Nuclear Proteins / metabolism*
Protein Binding
Receptors, G-Protein-Coupled / metabolism*
Signal Transduction
Smoothened Receptor
Zinc Finger Protein Gli2

Substances

FOXC1 protein, human
Forkhead Transcription Factors
GLI2 protein, human
Kruppel-Like Transcription Factors
Nuclear Proteins
Receptors, G-Protein-Coupled
SMO protein, human
Smoothened Receptor
Zinc Finger Protein Gli2

Abstract

Publication types

MeSH terms

Substances

Grants and funding