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环境内分泌干扰物促进乳腺细胞增殖的分子机制研究进展
林贞贤, 汝少国
中国海洋大学海洋生命学院
摘要:
乳腺癌是女性中常见的癌症,EDCs(environmental endocrine disrupting chemicals,环境内分泌干扰物)具有雌激素活性,能促进乳腺细胞的增殖,明确EDCs在乳腺癌细胞增殖中的作用和机制,有助于乳腺癌的预防。该研究在归纳整理国内外相关研究基础上,总结了EDCs通过激活雌激素受体信号通路、抑制细胞凋亡和改变细胞周期等方面促进乳腺细胞的增殖,并对其分子机制进行了全面综述。EDCs促进乳腺细胞增殖的分子机制有:①EDCs通过与雌激素核受体(nERs)结合形成二聚体,改变受体构象,并结合到靶基因雌激素响应元件上,进而调控增殖相关靶基因转录和蛋白表达;②EDCs也可通过与雌激素膜受体(mERs)结合,激活快速非基因组信号通路,改变靶蛋白活性或靶基因表达;③EDCs也可通过上调凋亡抑制蛋白Bcl-2和Bcl-xL的表达,抑制细胞凋亡;④EDCs还可通过上调细胞周期蛋白(cyclin)表达、提高周期依赖性蛋白激酶(CDKs)活性,加快细胞周期;⑤EDCs通过基因组、非基因组信号途径的交互,上调cyclin D和c-Myc表达,再通过CDK磷酸化细胞周期调节因子Rb蛋白,释放转录因子E2F,加速细胞从G1期向S期的转变,促进细胞增殖。建议今后从与内源激素交互、影响雌激素E2合成以及低剂量联合作用3个方面来探讨EDCs对乳腺细胞的增殖机制,以期为乳腺致癌物的筛查、乳腺癌预防和治疗以及乳腺细胞增殖机制的深入研究提供参考。
关键词:  环境内分泌干扰物  乳腺细胞  增殖  分子机制
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Research Advances on the Molecular Mechanism of Environmental Endocrine Disrupting Chemicals on Promoting Breast Cell Proliferation
Zhenxian Lin, Shaoguo Ru
Marine Life Science College,Ocean University of China
Abstract:
Abstract: Breast cancer is a common cancer in women. EDCs (environmental endocrine disrupting chemicals) have estrogenic activity and can promote breast cell proliferation. Therefore it is important to identify the role of EDCs in the proliferation of breast cancer cells and mechanisms for breast cancer prevention. Based on the summary of relevant researches in China and abroad, this study revealed that EDCs can promote the proliferation of breast cells by activating the estrogen receptor signaling pathway, inhibiting apoptosis and changing the cell cycle. This review summarized the molecular mechanisms of EDCs on promoting mammary cell proliferation as follows: (1)EDCs can bind with the estrogen nuclear receptors (nERs) to form dimers, change the receptor conformation, and bind to the estrogen response elements of the target genes, thereby regulating transcription and protein expression of proliferation-related target genes. (2)EDCs can activate rapid non-genomic signaling and alter target protein activity or target gene expression by binding to estrogen membrane receptors (mERs). (3)EDCs can inhibit cell apoptosis by up-regulating the expression of Bcl-2 and Bcl-xL. (4)EDCs can accelerate cell cycle by up-regulating the expression of cyclin, increasing the activity of CDKs. (5)EDCs can up-regulate the expression of cyclin D and c-Myc through the interaction of genomic and non-genomic signaling pathways, and then phosphorylate retinoblastoma protein (Rb) by CDK, releasing the transcription factor E2F, accelerating the transition from G1 phase to S phase and promoting cell proliferation. It is suggested that the mechanism of proliferation of EDCs on breast cells should be explored from three aspects: the interaction with endogenous hormones, the effect of estrogen E2 synthesis and the combination of low-dose mixture, which can provide better understanding of screening for breast carcinogens, breast cancer prevention and treatment and mammary gland cell proliferation mechanisms for further study.
Key words:  environmental endocrine disrupting chemicals  breast cell  proliferation  molecular mechanism