Fernandes S A F, Gomes G R O, Siu E R, Damas-Souza D M, Bruni-Cardoso A, Augusto T M, Lazari M F M, Carvalho H F, Porto C S
Section of Experimental Endocrinology, Department of Pharmacology, Universidade Federal de São Paulo - Escola Paulista de Medicina, INFAR, Vila Clementino, São Paulo, Brazil.
Int J Androl. 2011 Oct;34(5 Pt 1):486-500. doi: 10.1111/j.1365-2605.2010.01109.x. Epub 2010 Sep 27.
This study proposed to investigate further the role of oestrogens during pubertal growth of rat ventral prostate, by analysing the effect of anti-oestrogen fulvestrant (ICI 182,780) on the expression of androgen (AR) and oestrogen receptors (ESR1 and ESR2), mitogen-activated protein kinase (ERK1/2) phosphorylation, and expression of Ki-67, a biomarker for cell proliferation. Ventral prostates were obtained from 90-day-old rats treated once a week for 2 months with vehicle (control) or ICI 182,780 (10 mg/rat, s.c.). Transcripts for AR, ESR1 and ESR2 were evaluated by quantitative real-time polymerase chain reaction. Expression of AR, ESR1, ESR2, total and phospho-ERK1/2 was analysed by Western blot or immunofluorescence. Ki-67-positive cells and myosin heavy chain were detected by immunohistochemistry. Cylindrical epithelial cells slightly taller, epithelial dysplasia and an increase in smooth muscle layer were observed in the ventral prostate from ICI 182,780-treated rats. ICI 182,780 did not change the mRNA, but decreased the protein levels for AR in the ventral prostate. The expression of ESR1 (mRNA and protein) was upregulated by ICI 182,780, but no changes were observed on ESR2 expression (mRNA and protein). ICI 182,780 decreased the phosphorylation state of ERK1/2, with no changes in total ERK1/2 levels. Ki-67-positive cells in the ventral prostate were also decreased by ICI 182,780. In conclusion, ICI 182,780 induces downregulation of AR expression and may block the translocation of ESR1 and ESR2 from the nucleus to the plasma membrane, decreasing ERK1/2 phosphorylation and prostatic epithelial cell proliferation. These findings provide a basis for physiological roles of oestrogen in the ventral prostate. Further studies with fulvestrant are necessary in benign prostate hyperplasia and prostatic cancer models.
本研究旨在通过分析抗雌激素药物氟维司群（ICI 182,780）对雄激素受体（AR）和雌激素受体（ESR1和ESR2）表达、丝裂原活化蛋白激酶（ERK1/2）磷酸化以及细胞增殖生物标志物Ki-67表达的影响，进一步探究雌激素在大鼠腹侧前列腺青春期生长过程中的作用。从90日龄大鼠获取腹侧前列腺，每周一次给予溶媒（对照）或ICI 182,780（10 mg/大鼠，皮下注射），持续2个月。通过定量实时聚合酶链反应评估AR、ESR1和ESR2的转录本。采用蛋白质免疫印迹法或免疫荧光法分析AR、ESR1、ESR2、总ERK1/2和磷酸化ERK1/2的表达。通过免疫组织化学检测Ki-67阳性细胞和肌球蛋白重链。在接受ICI 182,780处理的大鼠腹侧前列腺中，观察到柱状上皮细胞略高、上皮发育异常和平滑肌层增加。ICI 182,780未改变腹侧前列腺中AR的mRNA水平，但降低了其蛋白水平。ICI 182,780上调了ESR1（mRNA和蛋白）的表达，但未观察到ESR2表达（mRNA和蛋白）的变化。ICI 182,780降低了ERK1/2的磷酸化状态，而总ERK1/2水平无变化。ICI 182,780也降低了腹侧前列腺中Ki-67阳性细胞的数量。总之，ICI 182,780诱导AR表达下调，并可能阻断ESR1和ESR2从细胞核向质膜的转运，降低ERK1/2磷酸化和前列腺上皮细胞增殖。这些发现为雌激素在腹侧前列腺中的生理作用提供了依据。在良性前列腺增生和前列腺癌模型中，有必要进一步开展氟维司群相关研究。
