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

Yu Tzu Chan; Alan C.Y. Lai; Ruey Jen Lin; Ya Hui Wang; Yi Ting Wang; Wen Wei Chang; Hsin Yi Wu; Yu Ju Lin; Wen Ying Chang; Jen Chine Wu; Jyh Cherng Yu; Yu Ju Chen; Alice L. Yu

doi:10.1002/ijc.32588

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

Yu Tzu Chan, Alan C.Y. Lai, Ruey Jen Lin, Ya Hui Wang, Yi Ting Wang, Wen Wei Chang, Hsin Yi Wu, Yu Ju Lin, Wen Ying Chang, Jen Chine Wu, Jyh Cherng Yu, Yu Ju Chen^*, Alice L. Yu

^*Corresponding author for this work

Graduate Institute of Biomedical Sciences

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

39 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1674-1685
Number of pages	12
Journal	International Journal of Cancer
Volume	146
Issue number	6
DOIs	https://doi.org/10.1002/ijc.32588
State	Published - 15 03 2020

Bibliographical note

Publisher Copyright:
© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC

Keywords

BAD
GPER
breast cancer stem cell
phosphoproteomics
tamoxifen

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "GPER-induced signaling is essential for the survival of breast cancer stem cells",

abstract = "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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AU - Chang, Wen Wei

AU - Wu, Hsin Yi

AU - Lin, Yu Ju

AU - Chang, Wen Ying

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AU - Yu, Jyh Cherng

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AU - Yu, Alice L.

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

Abstract

Bibliographical note

Keywords

UN SDGs

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