TY - JOUR
T1 - LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells
AU - Yue, Zhiying
AU - Yuan, Zengjin
AU - Zeng, Li
AU - Wang, Ying
AU - Lai, Li
AU - Li, Jing
AU - Sun, Peng
AU - Xue, Xiwen
AU - Qi, Junyi
AU - Yang, Zhengfeng
AU - Zheng, Yansen
AU - Fang, Yuanzhang
AU - Li, Dali
AU - Siwko, Stefan
AU - Li, Yi
AU - Luo, Jian
AU - Liu, Mingyao
N1 - Funding Information:
The authors thank Dihua Yu [M. D. Anderson Cancer Center (MDACC), Houston, TX, USA] for the gift of the MCF10A-ErbB2-14,3,3 cells; Hans Clevers (Hubrecht Institute for Developmental Biology and Stem Cell Research, Utrecht, The Netherlands) for the gift of the LGR4 expression plasmid; Qingyun (Jim) Liu (University of Texas Health Science Center, Houston, TX, USA) for the gift of the anti-LGR4 antibody; Hong Zhang (MDACC) for pathological consultation; and Yanqing Huang (Methodist Research Institute, Houston, TX, USA) for technical advice and assistance. This work was supported by National Key Research and Development Program of China Grant 2016YFC0902102 (to J.L.); the National Natural Science Foundation of China Grants 81722020, 81472048, and 81272911 (to J.L.), and 81330049 (to M.L.); the Innovation Program of Shanghai Municipal Education Commission Grant 14ZZ051 (to J.L.) and 2017-01-07-00-05-E00011 (to M.L.); Science and Technology Commission of Shanghai Municipality Grant 12ZR1447900 (to J.L.); U.S. National Institutes of Health, National Cancer Institute Grant R01CA204926 (to Y.L.); U.S. Department of Defense–Congressionally Directory Medical Research Program (DOD–CDMRP) Grant BC160240 (to Y.L. and M.L.); and the Fundamental Research Funds for the Central Universities (to J.L.). The authors declare no conflicts of interest.
Publisher Copyright:
© 2018 FASEB.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2018/5
Y1 - 2018/5
N2 - The fourth member of the leucine-rich repeat-containing GPCR family (LGR4, frequently referred to as GPR48) and its cognate ligands, R-spondins (RSPOs) play crucial roles in the development of multiple organs as well as the survival of adult stem cells by activation of canonical Wnt signaling. Wnt/β-catenin signaling acts to regulate breast cancer; however, the molecular mechanisms determining its spatiotemporal regulation are largely unknown. In this study, we identified LGR4 as a master controller of Wnt/β-catenin signaling-mediated breast cancer tumorigenesis, metastasis, and cancer stem cell (CSC) maintenance. LGR4 expression in breast tumors correlated with poor prognosis. Either Lgr4 haploinsufficiency or mammary-specific deletion inhibited mouse mammary tumor virus (MMTV)-PyMT- and MMTV-Wnt1-driven mammary tumorigenesis and metastasis. Moreover, LGR4 down-regulation decreased in vitro migration and in vivo xenograft tumor growth and lung metastasis. Furthermore, Lgr4 deletion in MMTV-Wnt1 tumor cells or knockdown in human breast cancer cells decreased the number of functional CSCs by ∼90%. Canonical Wnt signaling was impaired in LGR4-deficient breast cancer cells, and LGR4 knockdown resulted in increased E-cadherin and decreased expression of N-cadherin and snail transcription factor -2 (SNAI2) (also called SLUG), implicating LGR4 in regulation of epithelial-mesenchymal transition. Our findings support a crucial role of the Wnt signaling component LGR4 in breast cancer initiation, metastasis, and breast CSCs.
AB - The fourth member of the leucine-rich repeat-containing GPCR family (LGR4, frequently referred to as GPR48) and its cognate ligands, R-spondins (RSPOs) play crucial roles in the development of multiple organs as well as the survival of adult stem cells by activation of canonical Wnt signaling. Wnt/β-catenin signaling acts to regulate breast cancer; however, the molecular mechanisms determining its spatiotemporal regulation are largely unknown. In this study, we identified LGR4 as a master controller of Wnt/β-catenin signaling-mediated breast cancer tumorigenesis, metastasis, and cancer stem cell (CSC) maintenance. LGR4 expression in breast tumors correlated with poor prognosis. Either Lgr4 haploinsufficiency or mammary-specific deletion inhibited mouse mammary tumor virus (MMTV)-PyMT- and MMTV-Wnt1-driven mammary tumorigenesis and metastasis. Moreover, LGR4 down-regulation decreased in vitro migration and in vivo xenograft tumor growth and lung metastasis. Furthermore, Lgr4 deletion in MMTV-Wnt1 tumor cells or knockdown in human breast cancer cells decreased the number of functional CSCs by ∼90%. Canonical Wnt signaling was impaired in LGR4-deficient breast cancer cells, and LGR4 knockdown resulted in increased E-cadherin and decreased expression of N-cadherin and snail transcription factor -2 (SNAI2) (also called SLUG), implicating LGR4 in regulation of epithelial-mesenchymal transition. Our findings support a crucial role of the Wnt signaling component LGR4 in breast cancer initiation, metastasis, and breast CSCs.
KW - Epithelial-mesenchymal transition
KW - Mammary tumorigenesis
KW - Tumor progression
KW - Wnt
UR - http://www.scopus.com/inward/record.url?scp=85048631202&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048631202&partnerID=8YFLogxK
U2 - 10.1096/fj.201700897R
DO - 10.1096/fj.201700897R
M3 - Article
C2 - 29269400
AN - SCOPUS:85048631202
SN - 0892-6638
VL - 32
SP - 2422
EP - 2437
JO - FASEB Journal
JF - FASEB Journal
IS - 5
ER -