School of Medicine and Medical Science, UCD Conway Institute, St Vincent's University Hospital and University College Dublin, Dublin 4, Ireland.
Endocr Relat Cancer. 2010 Feb 18;17(1):255-64. doi: 10.1677/ERC-09-0216. Print 2010 Mar.
Epidemiological, clinical, and molecular studies suggest a role for oestrogen in thyroid cancer. How oestrogen mediates its effects and the consequence of it on clinical outcome has not been fully elucidated. The participation of coregulatory proteins in modulating oestrogen receptor (ER) function and input of crosstalk with the tyrosine kinase receptor HER2 was investigated. Oestrogen induced cell proliferation in the follicular thyroid cancer (FTC)-133 cells, but not in the anaplastic 8305C cell line. Knockdown of the coactivator steroid receptor coactivator (SRC)-1 inhibited FTC-133 basal, but not oestrogen induced, cell proliferation. Oestrogen also increased protein expression of SRC-1 and the ER target gene cyclin D1 in the FTC-133 cell line. ERalpha, ERbeta, the coregulatory proteins SRC-1 and nuclear corepressor (NCoR), and the tyrosine kinase receptor HER2 were localised by immunohistochemistry and immnofluorescence in paraffin-embedded tissue from thyroid tumour patients (n=111). ERalpha was colocalised with both SRC-1 and NCoR to the nuclei of the tumour epithelial cells. Expression of ERalpha and NCoR was found predominantly in non-anaplastic tumours and was significantly associated with well-differentiated tumours and reduced incidence of disease recurrence. In non-anaplastic tumours, HER2 was significantly associated with SRC-1, and these proteins were associated with poorly differentiated tumours, capsular invasion and disease recurrence. Totally, 87% of anaplastic tumours were positive for SRC-1. Kaplan-Meier estimates of disease-free survival indicated that in thyroid cancer, SRC-1 strongly correlates with reduced disease-free survival (P<0.001), whereas NCoR predicted increased survival (P<0.001). These data suggest opposing roles for the coregulators SRC-1 and NCoR in thyroid tumour progression.
流行病学、临床和分子研究表明，雌激素在甲状腺癌中起作用。雌激素如何介导其作用及其对临床结果的影响尚未完全阐明。本研究调查了调节雌激素受体（ER）功能的共激活蛋白和与酪氨酸激酶受体 HER2 交叉对话的作用。雌激素诱导滤泡性甲状腺癌细胞（FTC-133 细胞）增殖，但不诱导间变性 8305C 细胞系增殖。共激活蛋白类固醇受体共激活蛋白（SRC）-1 的敲低抑制 FTC-133 的基础，但不抑制雌激素诱导的细胞增殖。雌激素还增加了 FTC-133 细胞系中 SRC-1 和 ER 靶基因 cyclin D1 的蛋白表达。免疫组化和免疫荧光检测石蜡包埋的甲状腺肿瘤患者组织（n=111）中的 ERalpha、ERbeta、共激活蛋白 SRC-1 和核共抑制因子（NCoR）和酪氨酸激酶受体 HER2。ERalpha 与 SRC-1 和 NCoR 一起定位于肿瘤上皮细胞的核中。发现 ERalpha 和 NCoR 主要在非间变性肿瘤中表达，与分化良好的肿瘤和疾病复发率降低显著相关。在非间变性肿瘤中，HER2 与 SRC-1 显著相关，这些蛋白与低分化肿瘤、包膜浸润和疾病复发相关。总的来说，87%的间变性肿瘤对 SRC-1 呈阳性。无病生存的 Kaplan-Meier 估计表明，在甲状腺癌中，SRC-1 与无病生存时间缩短密切相关（P<0.001），而 NCoR 预测生存时间延长（P<0.001）。这些数据表明，共激活蛋白 SRC-1 和 NCoR 在甲状腺肿瘤进展中发挥相反的作用。
