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GPER 诱导的信号转导对于乳腺癌干细胞的存活至关重要。

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

机构信息

Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Taoyuan, Taiwan.

Institute of Biochemical Science, College of Life Science, National Taiwan University, Taipei, Taiwan.

出版信息

Int J Cancer. 2020 Mar 15;146(6):1674-1685. doi: 10.1002/ijc.32588. Epub 2019 Aug 7.

DOI:10.1002/ijc.32588
PMID:31340060
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7003894/
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.

摘要

G 蛋白偶联雌激素受体-1（GPER）是 G 蛋白偶联受体（GPCR）超家族的成员，介导雌激素诱导的正常和恶性乳腺上皮细胞增殖。然而，其在乳腺癌干细胞（BCSCs）中的作用尚不清楚。在这里，我们显示了三种 ER / PR 乳腺癌患者来源异种移植物中，BCSCs 中 GPER 的表达高于非 BCSCs。GPER 沉默降低了 BCSC 的干性特征，体外表现为乳腺球体形成能力降低，体内肿瘤生长减少，BCSC 群体减少。比较磷酸蛋白质组学显示，BCSCs 中 GPER 介导的 PKA/BAD 信号转导更为活跃。其配体，包括他莫昔芬（TMX），激活 GPER，诱导 PKA 和 BAD-Ser118 的磷酸化，以维持 BCSC 特性。转染显性失活突变 BAD（Ser118Ala）可导致细胞存活减少。综上所述，GPER 及其下游信号在维持 BCSC 的干性方面发挥着关键作用，这表明 GPER 是消除 BCSC 的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d09/7003894/f662cc715da7/IJC-146-1674-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d09/7003894/2acc401a13bb/IJC-146-1674-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d09/7003894/bae395d77094/IJC-146-1674-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d09/7003894/f3d8036ee3ed/IJC-146-1674-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d09/7003894/204de2052a47/IJC-146-1674-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d09/7003894/f662cc715da7/IJC-146-1674-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d09/7003894/2acc401a13bb/IJC-146-1674-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d09/7003894/bae395d77094/IJC-146-1674-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d09/7003894/f3d8036ee3ed/IJC-146-1674-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d09/7003894/204de2052a47/IJC-146-1674-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d09/7003894/f662cc715da7/IJC-146-1674-g005.jpg

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The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures.G蛋白偶联雌激素受体激动剂G-1抑制核雌激素受体活性并刺激新的磷酸化蛋白质组学特征。
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