GPER‐induced signaling is essential for the survival of breast cancer stem cells

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 expressi...

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Bibliographic Details
Published in:International journal of cancer 2020-03, Vol.146 (6), p.1674-1685
Main Authors: Chan, Yu‐Tzu, Lai, Alan C.‐Y., Lin, Ruey‐Jen, Wang, Ya‐Hui, Wang, Yi‐Ting, Chang, Wen‐Wei, Wu, Hsin‐Yi, Lin, Yu‐Ju, Chang, Wen‐Ying, Wu, Jen‐Chine, Yu, Jyh‐Cherng, Chen, Yu‐Ju, Yu, Alice L.
Format: Article
Language:English
Subjects:
Animals
BAD
bcl-Associated Death Protein - metabolism
Breast - pathology
Breast cancer
breast cancer stem cell
Breast Neoplasms - pathology
Cancer
Cell Line, Tumor
Cell proliferation
Cell Proliferation - drug effects
Cell survival
Cell Survival - drug effects
Cyclic AMP-Dependent Protein Kinases - metabolism
Epithelial cells
Estrogen receptors
Female
G protein-coupled receptors
Gene Knockdown Techniques
GPER
Humans
Medical research
Mice
Molecular Cancer Biology
Mutants
Neoplastic Stem Cells - pathology
phosphoproteomics
Phosphorylation
Phosphorylation - drug effects
Protein kinase A
Receptors, Estrogen - genetics
Receptors, Estrogen - metabolism
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Receptors, Progesterone - metabolism
Signal Transduction - drug effects
Spheroids, Cellular
Stem cells
Survival
Tamoxifen
Tamoxifen - pharmacology
Therapeutic applications
Transfection
Xenograft Model Antitumor Assays
Xenografts
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Summary: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. What's new? G protein‐coupled estrogen receptor‐1 (GPER) mediates estrogen‐induced proliferation of normal and malignant breast epithelial cells. However, the role of GPER in breast cancer stem cells (BCSC) biology remains unclear. Here, using patient‐derived xenografts of ER–/PR+ breast cancer, the authors found higher expression of GPER in BCSCs than non‐BCSCs. Moreover, the results indicated that stemness features were sustained via GPER‐mediated PKA/BAD phosphorylation. Stimulation by the GPER ligand tamoxifen enhanced BCSC cell viability and population and BAD phosphorylation. The findings revealed a vital role of GPER‐mediated signaling pathways in BCSC survival, suggesting GPER as a potential therapeutic target for eradicating BCSCs.
ISSN:0020-7136
1097-0215
1097-0215
DOI:10.1002/ijc.32588