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LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells
Author(s) -
Yue Zhiying,
Yuan Zengjin,
Zeng Li,
Wang Ying,
Lai Li,
Li Jing,
Sun Peng,
Xue Xiwen,
Qi Junyi,
Yang Zhengfeng,
Zheng Yansen,
Fang Yuanzhang,
Li Dali,
Siwko Stefan,
Li Yi,
Luo Jian,
Liu Mingyao
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700897r
Subject(s) - wnt signaling pathway , cancer research , metastasis , breast cancer , cancer stem cell , carcinogenesis , gene knockdown , stem cell , cancer , epithelial–mesenchymal transition , biology , medicine , oncology , signal transduction , microbiology and biotechnology , cell culture , genetics
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.—Yue, Z., Yuan, Z., Zeng, L., Wang, Y., Lai, L., Li, J., Sun, P., Xue, X., Qi, J., Yang, Z., Zheng, Y., Fang, Y., Li, D., Siwko, S., Li, Y., Luo, J., Liu, M. LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells. FASEB J. 32, 2422–2437 (2018). www.fasebj.org