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 & 4 others Partha S. Ray, Mien Chie Hung, Armando E. Giuliano, Xiaojiang Cui

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1046-1058
Number of pages13
JournalCell Reports
Volume13
Issue number5
DOIs
StatePublished - Nov 3 2015

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Chemical activation
Breast Neoplasms
Oncology
Transcription
Stem cells
Heterografts
Tumors
Transcription Factors
DNA
Epithelial-Mesenchymal Transition
Neoplastic Stem Cells
Mesoderm
Phenotype
Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Han, B., Qu, Y., Jin, Y., Yu, Y., Deng, N., Wawrowsky, K., ... Cui, X. (2015). FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer. Cell Reports, 13(5), 1046-1058. https://doi.org/10.1016/j.celrep.2015.09.063
Han, Bingchen ; Qu, Ying ; Jin, Yanli ; Yu, Yi ; Deng, Nan ; Wawrowsky, Kolja ; Zhang, Xiao ; Li, Na ; Bose, Shikha ; Wang, Qiang ; Sakkiah, Sugunadevi ; Abrol, Ravinder ; Jensen, Tor W. ; Berman, Benjamin P. ; Tanaka, Hisashi ; Johnson, Jeffrey ; Gao, Bowen ; Hao, Jijun ; Liu, Zhenqiu ; Buttyan, Ralph ; Ray, Partha S. ; Hung, Mien Chie ; Giuliano, Armando E. ; Cui, Xiaojiang. / FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer. In: Cell Reports. 2015 ; Vol. 13, No. 5. pp. 1046-1058.
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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.",
author = "Bingchen Han and Ying Qu and Yanli Jin and Yi Yu and Nan Deng and Kolja Wawrowsky and Xiao Zhang and Na Li and Shikha Bose and Qiang Wang and Sugunadevi Sakkiah and Ravinder Abrol and Jensen, {Tor W.} and Berman, {Benjamin P.} and Hisashi Tanaka and Jeffrey Johnson and Bowen Gao and Jijun Hao and Zhenqiu Liu and Ralph Buttyan and Ray, {Partha S.} and Hung, {Mien Chie} and Giuliano, {Armando E.} and Xiaojiang Cui",
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Han, B, Qu, Y, Jin, Y, Yu, Y, Deng, N, Wawrowsky, K, Zhang, X, Li, N, Bose, S, Wang, Q, Sakkiah, S, Abrol, R, Jensen, TW, Berman, BP, Tanaka, H, Johnson, J, Gao, B, Hao, J, Liu, Z, Buttyan, R, Ray, PS, Hung, MC, Giuliano, AE & Cui, X 2015, 'FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer', Cell Reports, vol. 13, no. 5, pp. 1046-1058. https://doi.org/10.1016/j.celrep.2015.09.063

FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer. / Han, Bingchen; Qu, Ying; Jin, Yanli; Yu, Yi; Deng, Nan; Wawrowsky, Kolja; Zhang, Xiao; Li, Na; Bose, Shikha; Wang, Qiang; Sakkiah, Sugunadevi; Abrol, Ravinder; Jensen, Tor W.; Berman, Benjamin P.; Tanaka, Hisashi; Johnson, Jeffrey; Gao, Bowen; Hao, Jijun; Liu, Zhenqiu; Buttyan, Ralph; Ray, Partha S.; Hung, Mien Chie; Giuliano, Armando E.; Cui, Xiaojiang.

In: Cell Reports, Vol. 13, No. 5, 03.11.2015, p. 1046-1058.

Research output: Contribution to journalArticle

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T1 - FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer

AU - Han, Bingchen

AU - Qu, Ying

AU - Jin, Yanli

AU - Yu, Yi

AU - Deng, Nan

AU - Wawrowsky, Kolja

AU - Zhang, Xiao

AU - Li, Na

AU - Bose, Shikha

AU - Wang, Qiang

AU - Sakkiah, Sugunadevi

AU - Abrol, Ravinder

AU - Jensen, Tor W.

AU - Berman, Benjamin P.

AU - Tanaka, Hisashi

AU - Johnson, Jeffrey

AU - Gao, Bowen

AU - Hao, Jijun

AU - Liu, Zhenqiu

AU - Buttyan, Ralph

AU - Ray, Partha S.

AU - Hung, Mien Chie

AU - Giuliano, Armando E.

AU - Cui, Xiaojiang

PY - 2015/11/3

Y1 - 2015/11/3

N2 - 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.

AB - 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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