突触核蛋白γ调控雌激素代谢酶CYP1B1诱导乳腺癌细胞增殖的机制研究

Originally discovered as breast cancer special gene,synuclein gamma(SNCG) is found to closely correlated with progression and drug-resistance of breast cancer.But the role in carcinogenesis of SNCG remains unclear.It is reported SNCG positively correlated with expression of CYP1B1in hormone-dependent tumors. CYP1B1 is a key enzyme catalyzing estrogens to genotoxic metabolites of estrogens that directly induce tumorigenesis. Mammary intraductal hyperplasia was detected in transgenic mice of overexpression of SNCG and CYP1B1 in our previous study.Furthermore,we found the knockdown and overexpression of SNCG induced decreasing and increasing the expression of CYP1B1. We propose hypothesis that by regulating CYP1B1, overexpression of SNCG leads to the excessive accumulation of genotoxic metabolites, causes the malignant proliferation of breast cancer cells.In this study,we will observe the expression of the two genes and their relationship by clinical cases analysis, study the effect on biological function of breast cancer cells and implanted tumor model, and further explore the mechanism of interactions between them. We aim to provide experimental basis to exploring the mechanism of SNCG and estrogens metabolic enzyme in breast cancer.

突触核蛋白γ（SNCG）被称为乳腺癌特异基因，与乳腺癌进展及化疗耐药密切相关。然而，其具体诱导乳腺癌发生的机制尚未明了。研究报道其与雌激素代谢酶CYP1B1在多数性激素依赖肿瘤中表达呈正相关。而CYP1B1恰是将雌激素代谢为具有“基因毒性”的4-羟基雌二醇的关键酶，后者可诱导肿瘤发生。我们前期研究结果发现两者共过表达转基因小鼠的乳腺导管上皮增生，细胞水平研究提示敲低或过表达SNCG均可引起CYP1B1相应变化。由此我们提出假说，SNCG通过调控CYP1B1表达，导致上述代谢产物过量生成，刺激乳腺细胞恶性增殖。本项目拟通过临床病理分析，明确两者在乳腺癌组织中的表达及相关性，再以体内及体外实验观察二者对癌细胞及移植瘤的具体生物学行为影响，最终探究两者相互作用方式，揭示SNCG调控CYP1B1表达的分子机制。从而为以SNCG及雌激素代谢酶为靶点探索乳腺癌发生机制提供实验依据。

突触核蛋白γ（SNCG）被称为乳腺癌特异基因，可诱导乳腺癌细胞增殖及对化疗药物耐药。其表达水平在乳腺癌中与雌激素4-羟基代谢酶CYP1B1成正相关。本研究拟探究SNCG与CYP1B1在乳腺癌中的表达和相互作用关系，并研究两者对乳腺癌细胞增殖等具体生物学行为影响。本研究发现，乳腺癌患者尿液中4羟基代谢产物较正常女性明显升高。且乳腺癌患者标本（手术切除癌组织、尿液中）SNCG、CYP1B1表达及含量水平均高于正常女性。在雌激素受体阳性乳腺癌细胞中，SNCG及CYP1B1表达水平明显升高。SNCG与CYP1B1协同作用细胞周期运转，凋亡减少，增强细胞增殖能力。在转基因小鼠中，SNCG及CYP1B1过表达小鼠的乳腺导管上皮细胞增生。在乳腺癌细胞系中，SNCG的表达变化影响CYP1B1表达水平。SNCG、CYP1B1参与调控PI3K/Akt/mTOR/VEGF/MAP信号通路影响乳腺癌细胞增殖。通过该研究SNCG、CYP1B1是影响乳腺癌细胞增殖的重要调节蛋白。