SUMO化修饰对AhR的调控及在乳腺癌发生、发展中的作用

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an estrogen-like hormone, but has greater toxicity that can induce the development of breast cancer. TCDD binds to the aromatic hydrocarbon receptor AhR (which belongs to the nuclear receptor superfamily) and regulates the subsequent expression of its downstream genes. Although the toxicity of TCDD has been investigated for many years, little is known about its molecular mechanism, which is difficult to study and has been considered as a hot research topic world-wide. Thus research focusing on how the activity of AhR can be regulated is a key link to understand the molecular mechanism of TCDD-induced breast cancer. Our preliminarily research has shown that AhR can be sumoylated, and sumoylation of AhR has a negative effect on its transcriptional activity. So further study will not only reveal the gene regulation network of nuclear receptor, but will also allow us to better understand the molecular mechanisms of transcriptional factors that are modified by SUMO in the generation and development of breast cancer. It may also provide new insight and target for potential breast cancer therapy.

二噁英TCDD是一种毒性较强的类雌激素物质，能诱导乳腺癌的发生。二噁英是通过与属于核受体家族成员的芳香烃受体AhR结合，进而调控AhR下游靶基因的表达来实现其功能的。对二噁英的毒性研究尽管进行了多年，但对其分子机理仍知之不多，是世界范围的研究热点和难点，因此研究AhR的活性是如何被调控的，是弄清TCDD诱导乳腺癌发生、发展分子机理非常重要的一环。我们的研究初步证明AhR是SUMO化修饰的靶蛋白，SUMO化修饰对AhR的转录活性起抑制作用，因此，进一步的研究，不仅可以揭示核受体的基因调控网络，还将有助于我们更好地了解转录相关因子的SUMO化修饰在乳腺癌发生、发展的分子机理，为乳腺癌的治疗提供新的思路和靶标。

肿瘤的发生、发展是遗传因素和环境因素相互作用的结果，雌激素分泌紊乱与多种妇科肿瘤，如乳腺癌、子宫内膜癌等密切相关。雌激素对妇科肿瘤有促进作用，它是通过雌激素受体介导的，本项目拟研究芳香烃受体AhR的一种重要的翻译后修饰，即SUMO化修饰与雌激素受体ERa及相关协同调节因子间的相互作用，进而探讨芳香烃受体对雌激素受体介导的基因表达调控，以及在肿瘤发生、发展中的作用。研究不仅可以揭示核受体的基因调控网络，还将有助于阐述雌激素相关生理及病理通路的分子机制，为肿瘤的治疗提供理论依据，为相关疾病的治疗开辟新的思路。