镉或/和硒的表观遗传效应与乳腺癌发生发展关系研究

We have found that cadmium or/and selenium are significantly associated with the risk and prognosis of breast cancer, but the intermediates are not known yet. Considering that the genetic toxicity of cadmium is weak, the carcinogenic pathway is likely through epigenetic changes, including DNA methylation, histone modification, and miRNA. Although other studies have found that cadmium or selenium is able to induce certain epigenetic changes, there are few studies involved in breast cells and it is unknown whether selenium can antagonize the epigenetic effects of cadmium. Moreover, the causal chain, cadmium or/and selenium →epigenetic changes → breast cancer, remains to be confirmed. This project will discover this “black box”. Firstly, by breast cell experiments, the epigenetic changes induced by cadmium or/and selenium would be obtained. Then, through literature searching and bioinformatic analyses, epigenetic biomarkers related to the risk and prognosis of breast cancer would be obtained and compared with the above experimental results, resulting in a set of overlapped epigenetic biomarkers suggesting potential intermediates between breast cancer and cadmium or/and selenium. Finally, using a case-control study and a patient cohort study, the relationships between these potential intermediates with the levels of cadmium/selenium and the risk or prognosis of breast cancer would be analyzed; whether the above causal chain exists would be confirmed; and the confirmed intermediate epigenetic biomarkers would be obtained. The results would provide references for the mechanisms of the induction of cadmium or/and selenium into breast cancer, and offer effective biomarkers for assessing the risk, screening, diagnosis, and prognosis prediction of breast cancer, as well as suggest potential targets for drug development on breast cancer prevention and treatment.

我们发现镉或硒及其交互作用显著影响乳腺癌风险或预后，但其中间环节不明。鉴于镉的遗传毒性弱，则其致癌途径可能是改变表观遗传(DNA甲基化、组蛋白修饰和miRNA)。尽管镉或硒可诱导某些表观遗传改变，但在乳腺细胞中研究甚少，硒是否拮抗镉的表观遗传效应也未可知，镉或/和硒→表观遗传→乳腺癌的因果链更有待证实。本项目首先采用乳腺细胞学实验，获得镉或/和硒诱导的表观遗传改变；再把这些改变与文献报道或由生物信息学方法获得的乳腺癌相关表观遗传改变比对，获得镉或/和硒致乳腺癌的潜在中间环节表观遗传标志物（重合部分）；最后通过病例对照和患者队列研究，分析这些潜在中间环节标志物与镉/硒水平和乳腺癌风险及预后的关系，证实上述因果链是否成立，并获得镉或/和硒致乳腺癌的中介表观遗传标志物，从而为解析其致癌机制提供参考，也为乳腺癌风险评估、筛检、诊断和预后估计提供有效标志物，为乳腺癌预防和治疗的药物开发提供潜在靶点。

鉴于镉或硒及其交互作用显著影响乳腺癌风险或预后，但其中间环节不明；且镉的遗传毒性弱，则其致癌途径可能是表观遗传(DNA甲基化、组蛋白修饰和miRNA)；尽管镉或硒可诱导某些表观遗传改变，但在乳腺细胞中研究甚少，硒是否拮抗镉的表观遗传效应也未可知，镉或/和硒→表观遗传→乳腺癌的因果链有待证实。本项目首先采用乳腺细胞学实验，获得镉或/和硒诱导的表观遗传改变；再把这些改变与文献报道或由生物信息学方法获得的乳腺癌相关表观遗传改变比对，获得镉或/和硒致乳腺癌的潜在中间环节表观遗传标志物（重合部分）；随后通过病例对照和患者队列研究，分析这些潜在中间环节标志物与镉/硒水平和乳腺癌风险及预后的关系，以证实上述因果链是否成立，并获得镉或/和硒致乳腺癌的中介表观遗传标志物。我们发现几种途径参与 Cd 诱导的乳腺癌发生，例如 Wnt 信号传导，代谢和人状瘤病毒（ HPV ）感染，TXNRD1和CCT3被鉴定为关键基因；NEDD4L和FMO5被鉴定为硒作用的关键基因；共有10个表观遗传调控基因介导了硒对镉的拮抗作用，包括APBA2、KIAA0895、DHX35、CPEB3、SVIL、MYLK、ZFYVE28、ABLIM2、GRB10和PCDH9，这些表观遗传调控基因参与多种癌症相关途径，如局灶性粘附和PI3K / Akt途径等。在人群研究中，我们发现GLS对乳腺癌的预后作用与H3K27me3的表达水平和更年期状态相关；乳腺癌组织中FOXA1对预后的预测存在时变效应；与绝经状态和病理特征相关的乳腺癌组织DNAm年龄是其预后的强大独立预测因素。这些结果为解析其硒镉与乳腺癌发生发展的关系提供了参考，也为乳腺癌风险评估、筛检、诊断和预后估计提供有效标志物，为乳腺癌预防和治疗的药物开发提供潜在靶点。