ArgBP2通过组蛋白修饰抑制ERα转录调控在乳腺癌进展及tamoxifen治疗抵抗中的作用

申请人首次报道了ArgBP2在胃癌里低表达，其上游转录因子通过招募甲基转移酶抑制ArgBP2转录，进而抑制胃癌细胞的增殖和迁移侵袭能力。但关于ArgBP2在乳腺癌中的作用从未有报道。抗雌激素治疗耐受和转移是雌激素受体α(Estrogen Receptor α, ERα)阳性乳腺癌治疗中面临的棘手问题，亟待发现新的有潜能的药物靶点。本课题预实验中发现，ArgBP2蛋白在乳腺癌组织中低表达，抑制乳腺癌细胞的增殖和迁移侵袭；并且ArgBP2与ERα在细胞内相互作用，并抑制ERE的转录活性。此外，ArgBP2能够增强细胞对抗雌激素治疗药Tamoxifen的敏感性。本项目拟在此基础上通过分子、细胞、动物模型及临床病例四个层面深入研究ArgBP2调控ERα转录活性的表观遗传学机制及其对抑制乳腺癌增殖、迁移侵袭以及抗雌激素治疗耐受中的作用，可望为乳腺癌临床治疗提供新的靶点。

We first reported that ArgBP2 showed low expression in gastric cancer samples and its transcription factor repressed ArgBP2 transcription by recruiting methyltransferase, thereby inhibiting proliferation, migration and invasion of gastric cancer cells. However, the role of ArgBP2 in breast cancer has never been reported. Resistance to anti-estrogen therapy and metastasis is a thorny issue in the treatment of ERα positive breast cancer, and it is urgent to find new potential drug targets. Our preliminary studies found that, ArgBP2 significantly decreased in breast cancer tissues, it inhibited the proliferation, migration and invasion of breast cancer cells; ArgBP2 interacted with ERα and suppressed the transcriptional activity of ERE. Besides, ArgBP2 enhanced the sensitivity of the cells to Tamoxifen, an anti-estrogen treatment. With experiments in molecular, cell, mouse model and clinical tissues, this project would further investigate the epigenetic mechanisms of ArgBP2 regulating ERα transcriptional activity and its role in inhibiting proliferation, migration and invasion of breast cancer as well as anti-estrogen treatment tolerance, and hopefully provide a new target for clinical treatment of breast cancer.