期刊
INTERNATIONAL JOURNAL OF CANCER
卷 146, 期 6, 页码 1674-1685出版社
WILEY
DOI: 10.1002/ijc.32588
关键词
GPER; breast cancer stem cell; phosphoproteomics; BAD; tamoxifen
类别
资金
- Ministry of Science and Technology in Taiwan [NSC102-2321-B-182A-005, MOST 103-2321-B-182A-002, MOST 104-2321-B-182A-004]
- Chang Gung Medical Foundation [OMRPG3C0012, OMRPG3C0013]
- Chang Gung Postdoctoral Fellowship Award
- Academia Sinica [97-2628-M-001-020-MY3]
G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER-/PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs.
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