Estrogen-independent activation of erbBs signaling and estrogen receptor α in the mouse vagina exposed neonatally to diethylstilbestrol
Estrogen-independent activation of erbBs signaling and estrogen receptor α in the mouse vagina exposed neonatally to diethylstilbestrol
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DOI：
10.1038/sj.onc.1207207
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发表时间：
2004-01-15
期刊：
影响因子：
8
通讯作者：
Iguchi, T
中科院分区：
文献类型：
--
作者：
Miyagawa, S;Katsu, Y;Iguchi, T
生长因子和雌激素受体（ER）信号通路协同作用，在小鼠生殖器官的细胞增殖、分化和肿瘤进展中发挥关键作用。用己烯雌酚（DES）处理新生小鼠会诱导阴道上皮出现不依赖雌激素的持续性增殖和角化，这在其生命后期会导致癌性病变。然而，雌激素依赖和非依赖通路的机制基本上仍不清楚。我们对表皮生长因子（EGF）样生长因子（EGF、转化生长因子α（TGF -α）、肝素结合性EGF样生长因子（HB - EGF）、β细胞素（BTC）、双调蛋白（APR）、上皮调节素（EPR）和神经调节蛋白（NRG）1）以及erbB受体（EGF受体（EGFR）、erbB/neu、erbB3和erbB4）在新生期（0 - 4天）或成年期（55 - 59天）用雌激素处理的小鼠阴道中的表达进行了研究。雌激素处理可激活小鼠阴道上皮中的EGFR和erbB2。在新生期暴露于DES的小鼠阴道中也观察到这种激活，同时伴有EGF、TGF -α、HB - EGF、BTC、APR、EPR和NRG1的表达。免疫组织化学分析表明，erbB2主要在阴道上皮中表达。最后，我们发现位于ERα的AF - 1结构域的丝氨酸118和167在这些阴道中被磷酸化。给予AG825、AG1478或ICI 182,780可阻断新生期DES暴露诱导的阴道上皮增殖。因此，通过EGFR和erbB2的信号转导可能与雌激素诱导的阴道变化以及持续的erbB磷酸化和EGF样生长因子的持续表达有关，从而导致ERα激活，这可能在新生期暴露于DES的小鼠生命后期导致阴道癌性病变。
Growth factors and estrogen receptor (ER) signaling cooperate to play essential roles in cell proliferation, differentiation and tumor progression in mouse reproductive organs. Treatment of neonatal mice with diethylstilbestrol (DES) induces an estrogen-independent persistent proliferation and cornification of the vaginal epithelium, which results in cancerous lesions later in life. However, the mechanisms of the estrogen-dependent and -independent pathways essentially remain unknown. We characterized the expression of epidermal growth factor (EGF)-like growth factors (EGF, transforming growth factor alpha (TGF-alpha), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), amphiregulin (APR), epiregulin (EPR) and neuregulin (NRG) 1) and erbB receptors (EGF receptor (EGFR), erbB/neu, erbB3 and erbB4) in the vaginae of mice treated either neonatally (0-4 day) or as adults (55-59 day) with estrogens. EGFR and erbB2 were activated in the vaginal epithelium of mice by estrogen treatment. This activation was also encountered in vaginae from neonatally DES-exposed mice, along with the expression of EGF, TGF-alpha, HB-EGF, BTC, APR, EPR and NRG1. Immunohistochemical analysis indicated that erbB2 was primarily expressed in vaginal epithelium. Finally, we found that serine 118 and 167 located in the AF-1 domain of ERalpha were phosphorylated in these vaginae. AG825, AG1478 or ICI 182,780 administration blocked proliferation of vaginal epithelium induced by neonatal DES exposure. Thus, signal transduction via EGFR and erbB2 could be related to the estrogen-induced vaginal changes and persistent erbBs phosphorylation and sustained expression of EGF-like growth factors, leading to ERalpha activation that may result in cancerous lesions in vaginae from neonatally DES-exposed mice later in life.