GPER-induced signaling is essential for the survival of breast cancer stem cells
GPER-induced signaling is essential for the survival of breast cancer stem cells
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DOI：
10.1002/ijc.32588
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发表时间：
2019-08-07
影响因子：
6.4
通讯作者：
Yu, Alice L.
中科院分区：
文献类型：
--
作者：
Chan, Yu-Tzu;Lai, Alan C. -Y.;Yu, Alice L.
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，可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3例患者来源的ER-/PR+乳腺癌异种移植物中，我们发现bscs中GPER的表达高于非bscs。GPER沉默降低了BCSC的干性特征，这反映在体外乳腺球形成能力的降低，以及BCSC种群减少的体内肿瘤生长。比较磷蛋白组学显示，bscs中gper介导的PKA/BAD信号传导更大。GPER通过其配体（包括他莫昔芬（TMX））激活，诱导PKA和BAD-Ser118磷酸化以维持BCSC特征。转染显性阴性突变体BAD （Ser118Ala）导致细胞存活率降低。综上所述，GPER及其下游信号在维持BCSCs的干性中起着关键作用，这表明GPER是根除BCSCs的潜在治疗靶点。
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.