Genistein alters growth factor signaling in transgenic prostate model (TRAMP)
Genistein alters growth factor signaling in transgenic prostate model (TRAMP)
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DOI：
10.1016/j.mce.2003.12.018
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发表时间：
2004-04-30
影响因子：
4.1
通讯作者：
Lamartiniere, CA
中科院分区：
文献类型：
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作者：
Wang, J;Eltoum, IE;Lamartiniere, CA
在转基因小鼠前列腺癌(TRAMP)模型中，大豆中的一种成分GeniSTEM被报道对自发发展的前列腺癌具有保护作用。这与报告显示，食用高大豆饮食的亚洲人降低了临床表现的前列腺癌的发病率是一致的。为了了解金雀异黄素的作用机制，我们从5周龄开始，研究了雄性激素和雌激素受体、四种通过酪氨酸蛋白激酶传递信号的生长因子受体和特异性生长因子蛋白在饲喂250 mg/kg饲料的不育小鼠前列腺背侧的表达。这些分析是在实体瘤发生前12周进行的，使我们能够容易地研究癌前组织中的细胞增殖和生物标记物。与C57BL/6小鼠相比，TRAMP小鼠前列腺细胞增殖、AR、ER-α、EGFR、ErbB2、EGF、IGF-1R、IGF-1、VEGFR2、ERKs-1和2蛋白及TGF-αmRNA显著增加，而ER-β和VEGF无明显变化。金雀异黄素显著抑制TRAMP小鼠前列腺细胞增殖、EGFR、IGF-1R、ERK-1和ERK-2，但对AR、ER-α、ER-β、ErbB2、EGF、TGF-α、IGF-1、VEGF和VEGFR无明显影响。饲喂对照或含染料木素饲料的C57BL/6或TRAMP雄性小鼠的血清睾酮和双氢睾酮浓度没有显著差异。TRAMP小鼠性类固醇受体和多种生长信号通路的上调支持多重失调致癌的概念。饮食中金雀异黄素下调酪氨酸激酶调节蛋白EGFR和IGF-1R以及下游丝裂原激活蛋白激酶ERK-1和2的表达，为前列腺癌的化学预防提供了可能的机制。(C)2003爱思唯尔爱尔兰有限公司。保留所有权利。
Genistem, a component of soy, has been reported to protect against spontaneously developing prostate tumors in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. This is consistent with reports showing that Asians eating a diet high in soy have reduced incidence of clinically manifested prostate cancer. In order to understand the mechanism of action of genistein, we have investigated the expression of androgen and estrogen receptors, four growth factor receptors that signal via tyrosine protein kinases, and specific growth factor proteins in the dorsolateral prostates of TRAMP mice fed 250 mg genistein/kg diet, starting at 5 weeks of age. These analyses were carried out at 12 weeks, prior to the development of solid tumors, allowing us to readily investigate cell proliferation and biomarkers in premalignant tissue. Cell proliferation, AR, ER-alpha, EGFR, ErbB2, EGF, IGF-1R, IGF-1, VEGFR2, ERKs-1 and 2 proteins and TGF-alpha mRNA, but not ER-beta and VEGF, were significantly increased in prostates of TRAMP compared to C57BL/6 mice. Genistein in the diet significantly down-regulated cell proliferation, EGFR, IGF-1R, ERK-1 and ERK-2, but not AR, ER-alpha, ER-beta, ErbB2, EGF, TGF-alpha, IGF-1 VEGF and VEGFR in prostates of TRAMP mice. Serum testosterone and dihydrotestosterone concentrations were not significantly different in C57BL/6 or TRAMP male mice fed control or genistein-containing diets. The up-regulation of sex steroid receptors and multiple growth signaling pathways in TRAMP mice supports the concept of multiple dysregulation contributing to carcinogenesis. Down-regulation of the tyrosine kinase regulated proteins, EGFR and IGF-1R, and of the downstream mitogen-activated protein kinases, ERK-1 and 2, with genistein in the diet provides a possible mechanism for prostate cancer chemoprevention. (C) 2003 Elsevier Ireland Ltd. All rights reserved.