锌指转录因子BCL6B-BCL6相互作用在乳腺癌发生发展的作用和机制及其临床应用价值研究

Recurrence and distant metastasis are the main causes of death in breast cancer patients, which involves oncogene activation and tumor suppressor gene inactivation. The transcriptional regulation by transcription factors is essential for gene expression regulation. Our preliminary studies found that BCL6B is down-regulated by promoter methylation in breast cancer. BCL6B had a tumor suppressor function and inhibited the oncogenesis and metastasis of breast cancer. BCL6B and BCL6 are highly homologous, and BCL6 is identified as an oncoprotein in breast cancer. The biological role of BCL6B in breast cancer is opposite of that of BCL6. With a variety of bioinformatics methods and preliminary studies, it is suggested that BCL6 and BCL6B can interact to each other. Therefore, we hypothesize that BCL6 and BCL6B are mutually antagonistic in the expression and molecular function in breast cancer. The imbalance of this interaction will promote the proliferation and metastasis of breast cancer cells. We will systematically study the role of BCL6B-BCL6 interaction in the development of breast cancer and the underlying molecular mechanism, determine whether BCL6B and BCL6 function interdependently; and evaluate the predictive value of combined detection of BCL6 and BCL6B for breast cancer metastasis. The outcomes of the study are important for elucidating the mechanism of breast cancer metastasis. The identified proteins may become a new marker for molecular diagnosis and prognosis evaluation of breast cancer, and provide an experimental basis for developing new breast cancer therapy strategies.

乳腺癌复发和远处转移是患者的主要死因。乳腺癌的发生发展涉及癌基因的激活和抑癌基因的失活，而转录因子参与的转录调控是基因表达调控的重要环节。我们前期研究发现BCL6B在乳腺癌中因启动子甲基化表达下调，具有抑癌功能，并可能抑制乳腺癌发生及转移。BCL6B 和BCL6高度同源，BCL6在乳腺癌中被确定为癌蛋白。BCL6B在乳腺癌中的生物学作用与BCL6截然相反。多种生物信息学方法及前期实验均提示BCL6和BCL6B可以相互作用。因此我们提出假说：乳腺癌组织中BCL6与BCL6B在表达及分子作用功能上相互对抗，该相互作用失衡则促进肿瘤细胞的增殖和转移。本项目拟系统探索BCL6B-BCL6相互作用参与乳腺癌发生发展的作用及分子机制；明确BCL6B 与BCL6的作用是否相互依赖；评价联合检测BCL6和BCL6B对乳腺癌转移的预测价值。研究所获得的蛋白有可能成为乳腺癌分子诊断、预后评价中的新标记分子。

乳腺癌是女性癌症死亡的主要原因。到目前为止，晚期乳腺癌仍缺乏有效的治疗策略和可靠的预后指标。本课题介绍了BCL6B（一种肿瘤抑制基因）在乳腺癌中的生理和病理功能及调控机制。由于启动子CpG甲基化，BCL6B在乳腺癌中经常沉默，其表达与乳腺癌患者的存活率呈正相关。BCL6B在乳腺癌中的抗肿瘤作用通过一系列体外和体内实验来阐明，包括细胞增殖，细胞凋亡，细胞周期停滞，上皮-间质转化（EMT）和裸鼠皮下瘤的生长。此外，BCL6B可以直接调节IFNAR以激活干扰素刺激的基因并增强巨噬细胞活化。乳腺癌细胞中异位BCL6B的表达可以下调CD24和CD47以促进巨噬细胞的吞噬作用，表明BCL6B有利于抗CD24和抗CD47的联合治疗，我们的研究结果揭示了BCL6B作为肿瘤抑制基因的作用模式，并提示BCL6B是乳腺癌中巨噬细胞吞噬作用的重要调节因子，有望为乳腺癌患者开发新的治疗策略。