Gao Hua, Xue Yake, Cao Lei, Liu Qian, Liu Chunhui, Shan Xiaosong, Wang Hongyun, Gu Yi, Zhang Yazhuo
Key Laboratory of Central Nervous System Injury Research, Center of Brain Tumor of Beijing Institute for Brain Disorders, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450003, China.
Mol Cell Endocrinol. 2017 Mar 5;443:32-41. doi: 10.1016/j.mce.2016.12.029. Epub 2016 Dec 31.
Estrogen has a key role in the pathogenesis of pituitary adenomas (PAs). The study was to evaluate the estrogen receptor alpha (ESR1) level in 289 PAs cases, its association with clinicopathologic features and serving as a target of cancer treatment. In this study, the ESR1 level was evaluated by tissue microarray (TMA). The effect of fulvestrant was determined by an animal model of prolactinoma established by subcutaneous injection of 17β-estradiol in F344 rats. The volume and weight of the pituitary were assessed in the different groups. The effects of fulvestrant on cell proliferation and cell invasion were explored in the pituitary adenoma cell lines GH3 and JT1-1. The ESR1-positive cells rates of 191/289 cases were more than 50%. And ESR1 high level cases (age≥50) were 103/133, and 88/156 in cases (age<50) (X = 14.17, p = 0.0001). The average weight of the pituitary gland in F344 rat tumor model induced by 17-β-estradiol was 38.6 ± 11.2 mg, almost 6 times higher than control group (6.2 ± 1.7 mg). Fulvestrant significantly reduced the weight of the pituitary and its inhibition rate was 68.4 ± 8.3%. TUNEL assay and Western blotting showed that fulvestrant induced apoptotic cell death in vivo and in vitro. PTEN/MAPK signaling pathways were activated in response to fulvestrant treatment in GH3 cells. U0126 partly rescued cell viability of GH3 cells after fulvestrant exposure. ESR1 can be a potential target for PAs, especially for elder GHomas and NFPAs. Fulvestrant may be a new choice for the treatment of PAs.
雌激素在垂体腺瘤（PA）的发病机制中起关键作用。本研究旨在评估289例PA病例中的雌激素受体α（ESR1）水平，其与临床病理特征的关联以及作为癌症治疗靶点的情况。在本研究中，通过组织微阵列（TMA）评估ESR1水平。通过在F344大鼠皮下注射17β-雌二醇建立的泌乳素瘤动物模型来确定氟维司群的作用。评估不同组中垂体的体积和重量。在垂体腺瘤细胞系GH3和JT1-1中探讨氟维司群对细胞增殖和细胞侵袭的影响。289例病例中191例的ESR1阳性细胞率超过50%。ESR1高水平病例（年龄≥50岁）为103/133例，（年龄<50岁）病例中为88/156例（X = 14.17，p = 0.0001）。17-β-雌二醇诱导的F344大鼠肿瘤模型中垂体的平均重量为38.6±11.2mg，几乎是对照组（6.2±1.7mg）的6倍。氟维司群显著降低了垂体重量，其抑制率为68.4±8.3%。TUNEL检测和蛋白质印迹法表明氟维司群在体内和体外均诱导凋亡性细胞死亡。在GH3细胞中，氟维司群处理后PTEN/MAPK信号通路被激活。氟维司群处理后，U0126部分挽救了GH3细胞的活力。ESR1可能是PA的潜在靶点，尤其是对于老年生长激素瘤和无功能垂体腺瘤。氟维司群可能是PA治疗的新选择。
