雌激素受体调控ATBF1蛋白定位的功能及分子机制研究

ATBF1 is a candidate tumor suppressor gene in breast cancer. Recent years, localization of ATBF1 in multiple tumors was attracted because of its correlation with clinical indexes. However, function and mechanism of ATBF1 localization in breast cancer was rarely reported. Our previous studies have found that ATBF1 took parts in multiple hormone-hormone receptor signaling pathways. In estrogen-estrogen receptor (E2-ER) pathway, ATBF1 was demonstrated to regulate ER target gene expression to inhibit cell proliferation. Meanwhile, ATBF1 expression was regulated by ER in a feedback mechanism. Our preliminary results showed that ATBF1 protein was transferred from cytoplasm to nuclear, along with the translocation of ER under E2 treatment. In the present study, our purpose was to investigate function of ATBF1 localization to breast epithelial cell proliferation in E2-ER pathway and effect of ER on ATBF1 localization. We plan to detect localization of ATBF1 and ER in breast cancer cell lines and clinical samples, and analyze statistical significance. Next, the effect of ATBF1 localization on cell proliferation and oncogenesis under activation of E2-ER pathway will be assessed in cell lines in vitro and in tumor-bearing model in vivo. The effect of ER on ATBF1 localization and the mechanism will be further investigated. This work provides a novel insight to investigate the function of ATBF1 in ER positive breast cancer and ATBF1 localization regulated by ER may provide a novel target site for endocrine therapy.

ATBF1是乳腺癌的一个候选抑癌基因。近年来，研究人员发现ATBF1蛋白定位与多种肿瘤诊断预后指标相关，但乳腺癌中ATBF1 蛋白定位的功能，特别是分子机制尚无文献报道。我们前期研究发现，乳腺上皮细胞中，ATBF1参与调控多条激素及其受体信号通路，特别是在E2-ER通路中，ATBF1与ER相互调节，形成自动反馈回路，维持乳腺上皮细胞稳态。前期结果显示，E2处理后ER由细胞浆转入细胞核，同时ATBF1蛋白也发生相应定位变化，提示ER可能通过调控ATBF1蛋白定位影响细胞增殖。本项目拟分别在乳腺癌细胞系和乳腺癌临床样本中检测ATBF1、ER蛋白定位，统计分析二者之间及其与乳腺上皮细胞增殖的关系；进一步在体外细胞模型和体内裸鼠模型中通过改变不同定位的ATBF1 蛋白表达揭示ATBF1 蛋白定位对ER介导的乳腺上皮细胞增殖及乳腺成瘤的影响，并深入探索ER调控ATBF1 蛋白定位的分子机制。

乳腺癌是危害女性健康最主要的一类恶性肿瘤，研究乳腺癌的发病机理对于分子诊断和治疗具有重要意义。ATBF1是乳腺癌的一个候选抑癌基因。近年来，研究人员发现ATBF1蛋白定位与多种肿瘤诊断预后指标相关，但乳腺癌中ATBF1的蛋白定位及功能鲜有研究报道。本研究基本完成了项目要求的主要技术指标和研究内容，基本完成了项目预期成果。主要研究内容及成果包括：1. 乳腺癌临床样本中检测ATBF1表达发现，肿瘤组织中ATBF1 mRNA及蛋白水平均显著低于癌旁正常组织；2. 肿瘤组织中ATBF1 mRNA及蛋白表达水平均与临床病理参数（肿瘤分级）显著相关，与其它病理参数（肿瘤大小、ER、PR、淋巴结转移等）无显著相关性；3. ATBF1蛋白在肿瘤组织中主要表达于细胞浆，而在正常组织中主要表达于细胞核；4. 肿瘤组织中，细胞核定位的ATBF1与细胞浆定位的ATBF1表达均随着肿瘤分级升高而显著下调，且ATBF1蛋白核浆比也与肿瘤分级呈显著负相关；5.ATBF1蛋白的定位变化受雌激素及其受体的调控；6. ATBF1表达受TGF-β及其信号通路的调节，进而影响乳腺上皮细胞的上皮间质转化，影响细胞迁移；7. 本研究发表SCI研究论文3篇，国内核心期刊论文1篇。