GPER-mediated proliferation and estradiol production in breast cancer-associated fibroblasts.
GPER-mediated proliferation and estradiol production in breast cancer-associated fibroblasts.
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GPER 介导的乳腺癌相关成纤维细胞的增殖和雌二醇的产生。
DOI：
10.1530/erc-13-0237
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发表时间：
2014-04
影响因子：
3.9
通讯作者：
Tu G
中科院分区：
文献类型：
--
作者：
Luo H;Yang G;Yu T;Luo S;Wu C;Sun Y;Liu M;Tu G
癌症相关成纤维细胞（CAF）是乳腺癌进展的重要共同介质。雌激素是乳腺细胞外基质循环调节的主要驱动力，因此可能影响肿瘤相关基质。最近，第三种雌激素受体，雌激素（G蛋白偶联）受体（GPER），已被报道在乳腺CAFs中表达。本研究采用免疫组化方法检测了41.8%（59/141）的原发性乳腺癌间质成纤维细胞中GPER的表达。通过免疫染色和RT-PCR分析证实了GPER在从原发性乳腺癌组织中分离的CAFs中的表达。除了17β-雌二醇（E2）和GPER激动剂G1外，他莫昔芬（TAM）也可激活GPER，导致细胞指数、细胞内钙和ERK 1/2磷酸化的短暂增加。此外，TAM，E2和G1促进CAF增殖和细胞周期进程，这两者都被GPER干扰，选择性GPER拮抗剂G15，表皮生长因子受体（EGFR）抑制剂AG 1478和ERK 1/2抑制剂U 0126阻断。重要的是，当E2的底物睾酮加入培养基中时，TAM和G1通过GPER/EGFR/ERK信号增加乳腺CAFs中E2的产生。GPER诱导的芳香化酶上调可能是造成这种现象的原因，因为TAM和G1诱导的CYP 19 A1基因表达被GPER敲低和G15、AG 1478和U 0126给药降低。因此，GPER介导的CAF依赖性雌激素对肿瘤相关间质的作用是可以想象的，并且CAF可能通过涉及GPER/EGFR/ERK信号传导和E2产生的正反馈回路促进乳腺癌进展，特别是TAM抗性。
Cancer-associated fibroblasts (CAFs) are crucial co-mediators of breast cancer progression. Estrogen is the predominant driving force in the cyclic regulation of the mammary extracellular matrix, thus potentially affecting the tumor-associated stroma. Recently, a third estrogen receptor, estrogen (G-protein-coupled) receptor (GPER), has been reported to be expressed in breast CAFs. In this study, GPER was detected by immunohistochemical analysis in stromal fibroblasts of 41.8% (59/141) of the primary breast cancer samples. GPER expression in CAFs isolated from primary breast cancer tissues was confirmed by immunostaining and RT-PCR analyses. Tamoxifen (TAM) in addition to 17β-estradiol (E2) and the GPER agonist G1 activated GPER, resulting in transient increases in cell index, intracellular calcium, and ERK1/2 phosphorylation. Furthermore, TAM, E2, and G1 promoted CAF proliferation and cell-cycle progression, both of which were blocked by GPER interference, the selective GPER antagonist G15, the epidermal growth factor receptor (EGFR) inhibitor AG1478, and the ERK1/2 inhibitor U0126. Importantly, TAM as well as G1 increased E2 production in breast CAFs via GPER/EGFR/ERK signaling when the substrate of E2, testosterone, was added to the medium. GPER-induced aromatase upregulation was probably responsible for this phenomenon, as TAM- and G1-induced CYP19A1 gene expression was reduced by GPER knockdown and G15, AG1478, and U0126 administration. Accordingly, GPER-mediated CAF-dependent estrogenic effects on the tumor-associated stroma are conceivable, and CAF is likely to contribute to breast cancer progression, especially TAM resistance, via a positive feedback loop involving GPER/EGFR/ERK signaling and E2 production.