Modulation of aromatase expression in human breast tissue
Modulation of aromatase expression in human breast tissue
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DOI：
10.1016/s0960-0760(01)00132-7
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发表时间：
2001-12-01
影响因子：
4.1
通讯作者：
Itoh, T
中科院分区：
文献类型：
--
作者：
Chen, SU;Zhou, DJ;Itoh, T
芳香化酶通过其在雌激素合成中的作用在乳腺癌的发展中起重要作用。乳腺组织中芳香化酶的表达可以通过几种机制来调节。乳腺肿瘤中芳香化酶表达的主要启动子（即cAMP刺激的启动子1.3和II）与正常乳腺组织中的启动子（即糖皮质激素刺激的启动子1.4）不同。最近对与启动子1.3和11附近的两个重要调控元件（即SI和CREaro）相互作用的转录因子的表征有助于我们更好地理解正常乳腺组织和癌组织之间启动子使用的转换机制。据认为，在正常乳腺组织中，启动子1.3和11的功能是通过α-2、COUP-TFI和EARgamma与S1的结合，以及通过Snail/Slug蛋白与它们的结合位点的结合而被抑制的，所述结合位点淬灭CREaro活性。在癌组织中。EAR-2、COUP-TFI、EAR γ、Snail和Slug的表达水平降低，然后通过ERR α-1与S1的结合和CREB或相关因子与CREaro的结合上调芳香酶表达。该实验室和其他实验室的结果表明，芳香酶表达细胞中的芳香酶活性也可以通过用芳香酶抑制剂和抗雌激素ICI 182，780治疗来改变。虽然芳香酶抑制剂用于治疗乳腺癌，但已发现该治疗可增加某些患者乳腺组织中芳香酶的水平。芳香酶抑制剂对芳香酶活性的增强被认为是由于酶-抑制剂复合物的形成减少了芳香酶蛋白的降解，通过cAMP介导的机制上调了芳香酶基因的转录，以及促性腺激素诱导了芳香酶的表达，促性腺激素响应绝经前妇女循环中雌激素水平的降低而从垂体释放。已发现抗雌激素ICI 182，780抑制芳香化酶表达，但其机制尚未确定。此外，芳香化酶的活性和表达可能受到环境化学物质的影响。详细的结构-功能研究表明，黄酮类化合物是芳香化酶的抑制剂，但不包括黄酮类化合物。有人发现，黄酮类化合物结合到芳香化酶的活性位点的方向，其中它们的环-A和-C模仿环-D和-C的雄激素底物。内分泌干扰化学品对芳香酶表达的调节以两种有机氯农药（即毒杀芬和氯代灭幼脲）为例，已发现它们是ERR α-1孤儿受体的拮抗剂。这些化合物降低ERR α-1活性，导致芳香酶表达的抑制。(C)2002年由Elsevier Science Ltd.出版
Aromatase plays an important role in breast cancer development through its role in the synthesis of estrogen. Aromatase expression in breast tissue can be regulated by several mechanisms. The major promoter usage for aromatase expression in breast tumors (i.e, cAMP-stimulated promoters 1.3 and II) is different from that in normal breast tissue (i.e. glucocorticoid-stimulated promoter 1.4). Recent characterization of transcription factors that interact with the two important regulatory elements near promoters 1.3 and 11, i.e. SI and CREaro, helps us better understand the mechanism of the switch of promoter usage between normal breast tissue and cancer tissue. It is thought that in normal breast tissue, the function of promoters 1.3 and 11 is suppressed through the binding of EAR-2, COUP-TFI, and EARgamma to S1, and through the binding of Snail/Slug proteins to their binding site that quenchs the CREaro activity. In cancer tissue. the expression levels of EAR-2, COUP-TFI, EARgamma, Snail, and Slug decrease, and aromatase expression is then up regulated through the binding of ERRalpha-1 to S1 and the binding of CREB or related factors to CREaro. Results from this and other laboratories reveal that aromatase activity in aromatase expressing cells can also be modified by treatment with aromatase inhibitors and the antiestrogen ICI 182, 780. While aromatase inhibitors are used to treat breast cancer, the treatment has been found to increase the level of aromatase in the breast tissue of some patients. The enhancement of aromatase activity by aromatase inhibitors is thought to be due to a decrease of aromatase protein degradation by enzyme-inhibitor complex formation, up-regulation of the aromatase gene transcription through a cAMP-mediated mechanism, and an induction of aromatase expression by gonadtropins that axe released from the pituitary in response to a reduction of estrogen levels in circulation in premenopausal women. Antiestrogen ICI 182, 780 has been found to suppress aromatase expression, but the mechanism has not yet been determined. In addition, aromatase activity and expression can be affected by environmental chemicals. A detailed structure-function study has revealed that flavones, but not isoflavones, are inhibitors of aromatase. It was found that flavones bind to the active site of aromatase in an orientation in which their rings-A and -C mimic rings-D and -C of the androgen substrate. The modulation of aromatase expression by endocrine disrupting chemicals is exemplified by two organochlorine pesticides (i.e. toxaphene and chlordane) that have been found to be antagonists of ERRalpha-1 orphan receptor. These compounds reduce ERRalpha-1 activity, resulting in a suppression of aromatase expression. (C) 2002 Published by Elsevier Science Ltd.