title: FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer.
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.
authors.affiliation: Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Bingchen
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Biostatistics and Bioinformatics Research Center, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Deng
authors.affiliation: Department of BioMedical Sciences, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Kolja
authors.initials: K
authors.lastname: Wawrowsky
authors.affiliation: Biostatistics and Bioinformatics Research Center, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Pathology, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Shikha
authors.initials: S
authors.lastname: Bose
authors.affiliation: Department of Medicine, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Sugunadevi
authors.initials: S
authors.lastname: Sakkiah
authors.affiliation: 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.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Abrol
authors.affiliation: Department of Surgery, University of Illinois College of Medicine at Urbana Champaign, Urbana, IL 61801, USA.
authors.forename: Tor W
authors.initials: TW
authors.lastname: Jensen
authors.affiliation: Department of Medicine, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Berman
authors.affiliation: Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Bowen
authors.initials: B
authors.lastname: Gao
authors.affiliation: College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Jijun
authors.initials: J
authors.lastname: Hao
authors.affiliation: Biostatistics and Bioinformatics Research Center, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Zhenqiu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Ralph
authors.initials: R
authors.lastname: Buttyan
authors.affiliation: Department of Surgery, University of Illinois College of Medicine at Urbana Champaign, Urbana, IL 61801, USA.
authors.forename: Partha S
authors.initials: PS
authors.lastname: Ray
authors.affiliation: 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.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Armando E
authors.initials: AE
authors.lastname: Giuliano
authors.affiliation: 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.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Cui
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2
chemical_list: C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; C082593:GLI2 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2