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

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 ButtyanPartha S. Ray, Mien Chie Hung, Armando E. Giuliano, Xiaojiang Cui

Research output: Contribution to journal › Article › peer-review

124 Scopus citations

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 language	English (US)
Pages (from-to)	1046-1058
Number of pages	13
Journal	Cell Reports
Volume	13
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2015.09.063
State	Published - Nov 3 2015

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

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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, T. W., Berman, B. P., Tanaka, H., Johnson, J., Gao, B., Hao, J., Liu, Z., ... 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

@article{ed31662d75654b72a8125ee2e92f6333,

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.",

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",

note = "Publisher Copyright: {\textcopyright} 2015 The Authors.",

year = "2015",

month = nov,

day = "3",

doi = "10.1016/j.celrep.2015.09.063",

language = "English (US)",

volume = "13",

pages = "1046--1058",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "5",

}

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

TY - JOUR

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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U2 - 10.1016/j.celrep.2015.09.063

DO - 10.1016/j.celrep.2015.09.063

M3 - Article

C2 - 26565916

AN - SCOPUS:84947443777

SN - 2211-1247

VL - 13

SP - 1046

EP - 1058

JO - Cell Reports

JF - Cell Reports

IS - 5

ER -

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

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