溴结构域蛋白BRD4促进三阴性乳腺癌恶性生物学行为的机制研究

三阴性乳腺癌由于缺乏激素和Her2受体，靶向及内分泌治疗等治疗方法收效甚微，导致复发率高、侵袭性强、死亡率高，相较于其他类型的乳腺癌具有最差的预后，因此，寻找新的有效治疗方法成为当前亟需解决的科学问题。溴结构域蛋白BRD4目前是治疗肿瘤的热门靶点，其可以通过转录调控及染色质重塑参与调控肿瘤的发生发展。我们的研究结果发现BRD4在TNBC细胞株及预后差的患者肿瘤组织中高表达，体内及体外实验证实BRD4可以促进TNBC细胞的增殖及侵袭转移等恶性生物学行为，去甲基化酶ALKBH5在此过程中起重要的介导作用，以上结果提示BRD4可以作为TNBC治疗的重要潜在靶点。本项目拟确证BRD4在促进TNBC增殖、侵袭转移，内分泌治疗抵抗等生物学行为中的作用，以ALKBH5为切入点，深入解析其上下游分子机制，系统评价以BRD4为靶点治疗TNBC的可行性，为TNBC的临床治疗提供具有重大潜力的治疗靶点。

Due to the lack of hormones and HER2 receptors, targeting and endocrine therapy have little effect on triple-negative breast cancer, leading to high recurrence rate, strong invasion ability and high mortality. Compared with other types of breast cancer, triple-negative breast cancer has the worst prognosis. Therefore, finding new effective treatment methods has become a scientific problem that needs to be solved at present. Bromodomain-containing protein 4 is currently a popular target for the treatment of tumors, and it can participate in the regulation of tumor development through transcriptional regulation and chromatin remodeling. Our results found the expression of BRD4 in TNBC cell lines and tumor tissue of patients are high. Vivo and vitro experiments have verified that BRD4 can promote TNBC cell proliferation and invasion , demethylase ALKBH5 playing a mediating role in this process, the above results suggesting that BRD4 can serve as a important potential target in TNBC treatment. This project aims to confirm the role of BRD4 in promoting TNBC proliferation, metastasis, endocrine therapy resistance and other biological behaviors. Taking ALKBH5 as the entry point, deeply analyse the upstream and downstream molecular mechanisms and systematically evaluate the feasibility of BRD4 as the target for treating TNBC , so as to provide a potential therapeutic target for the clinical treatment of TNBC.