Effects of the estrogen receptor antagonist fulvestrant on F344 rat prolactinoma models
Effects of the estrogen receptor antagonist fulvestrant on F344 rat prolactinoma models
复制标题
雌激素受体拮抗剂氟维司群对F344大鼠泌乳素瘤模型的影响
DOI：
10.1007/s11060-013-1351-8
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发表时间：
2014-02-01
影响因子：
3.9
通讯作者：
Zhang, Yazhuo
中科院分区：
文献类型：
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作者：
Cao, Lei;Gao, Hua;Zhang, Yazhuo
雌激素和泌乳素瘤之间的关系是有据可查的。但单纯的雌激素受体拮抗剂氟维司群对泌乳素瘤的抗肿瘤作用，尤其是体内抗肿瘤作用，及其可能的机制尚不清楚。因此，本研究的目的是评价氟维司群对大鼠泌乳素瘤模型的影响以及Wnt信号通路的参与。雌性F344大鼠40只，皮下注射17β-雌二醇10 mg，连续6周，建立催乳素瘤模型。给大鼠肌内注射氟维司群（0、0.5、3、20、40 mg/kg），在氟维司群给药前和给药后第3、7和14天评价肿瘤大小、重量和血清催乳素（PRL）水平。采用定量PCR和蛋白质印迹法检测泌乳素腺瘤中雌激素受体α（ERα）、β-catenin和Wnt抑制因子-1（WIF-1）的表达，并采用焦磷酸测序法检测WIF-1启动子甲基化。氟维司群处理后，肿瘤大小、重量和血清PRL水平以剂量依赖性和时间依赖性方式受到抑制。氟维司群治疗后，β-连环蛋白表达下调，但WIF-1表达上调。WIF-1启动子CpG位点甲基化与WIF-1表达呈负相关。此外，氟维司群对GH 3细胞的抗细胞增殖作用被Wnt信号通路激动剂SB 216763部分破坏。总之，氟维司群通过ERα抑制催乳素瘤的肿瘤增殖和PRL分泌，Wnt信号通路参与了这种抗肿瘤作用。因此，氟维司群可能是一种潜在的治疗泌乳素瘤的新药。
The relationship between estrogen and prolactinoma is well documented. But the anti-tumor effects of a pure estrogen receptor antagonist fulvestrant on prolactinomas, especially in vivo, and the possible mechanisms are still unclear. Therefore, the aim of this study was to evaluate the effects of fulvestrant and the involvement of the Wnt signaling pathway on rat prolactinoma models. Forty female F344 rat prolactinoma models were established by subcutaneous administration of 10 mg 17β-estradiol for 6 weeks. Rats were intramuscularly injected with fulvestrant (0, 0.5, 3, 20, 40 mg/kg), and tumor size, weight and serum prolactin (PRL) levels were evaluated before and after fulvestrant treatment at 3, 7 and 14 days. Expression of estrogen receptor α (ERα), β-catenin and Wnt inhibitory factor-1 (WIF-1) in prolactinomas was measured using quantitative PCR and western blotting, and methylation of the WIF-1 promoter was investigated using pyrosequencing. Tumor size, weight and serum PRL levels were inhibited in dose-dependent and time-dependent manners after fulvestrant treatments. β-catenin expression was downregulated but WIF-1 expression was upregulated following fulvestrant treatment. The methylation of the CpG site of the WIF-1 promoter was negatively correlated to the expression of WIF-1. In addition, the anti-cell proliferation of fulvestrant on GH3 cells was partly disrupted by Wnt signaling pathway agonist SB 216763. In conclusion, fulvestrant inhibited tumor proliferation and PRL secretion of prolactinomas via ERα, and the Wnt signaling pathway was involved in this anti-tumor effect. Therefore, fulvestrant may be a potential new drug for prolactinomas.