吐根素通过阻断Wnt信号通路抑制乳腺癌的作用机制

The Wnt signaling pathway plays an important roles in breast cancer metastasis and maintaining characteristics of cancer stem cells. In Our pilot studies demonstrate that a natural alkaloid emetine used as an anti-amoebiasis drug is a novel inhibitor of Wnt signaling, which can inhibit the formation of microspheres in breast cancer stem cell. In this proposal, we will characterize the Wnt inhibitory function of emetine and explore potential mechanisms by which emetine inhibits the Wnt signaling cascade in breast cancer cells. In addition, we will determine whether emetine is able to inhibit the migration and invasion of breast cancer cells by targeting Wnt signaling. Furthermore, we will test whether emetine can prevent breast cancer in MMTV-Wnt1 transgenic mice. Using MMTV-Wnt1 transgenic mouse model we will directly test the Wnt inhibitory function of emetine in vivo, and assess the efficacy of emetine on Wnt-driven breast cancer. We will isolate breast cancer stem cells from MMTV-Wnt1 transgenic mouse. These cells will be employed to test the effect of emetine on Wnt signaling, sphere formation and tumorgenesis. In conclusion, this project will clarify the molecular mechanism underlying anti-breast cancer activity of emetine through blocking the Wnt signaling pathway. This study will provide new insights to the design and development of therapeutic strategy for targeting Wnt-driven cancer.

Wnt信号通路与肿瘤干细胞的形成，以及乳腺肿瘤的发生发展密切相关。本项目的前期研究发现：抗阿米巴原虫病的老药吐根素能够抑制Wnt信号通路和乳腺癌干细胞的微球体形成。本项目将系统地研究吐根素抑制Wnt信号通路的具体作用靶点，探索吐根素调控Wnt信号在乳腺癌细胞迁移和浸润中的作用机制；建立小鼠乳腺癌肺转移模型，评价吐根素对乳腺癌转移的影响；利用MMTV-Wnt1转基因小鼠模型确定吐根素是否抑制Wnt1诱导的乳腺癌的发生发展，并从该转基因小鼠模型中分离乳腺癌干细胞，观察吐根素对这些乳腺癌干细胞生物活性的影响。通过本项目研究，揭示吐根素抑制Wnt信号通路、乳腺癌发生发展及转移、乳腺癌干细胞活性的作用机制，为乳腺癌的治疗提供一种潜在的新策略。

Wnt信号通路与肿瘤干细胞的形成，以及乳腺肿瘤的发生发展密切相关。本项目研究发现：抗阿米巴原虫病的老药吐根素能够抑制Wnt信号通路和乳腺癌干细胞的微球体形成。我们系统地研究吐根素抑制Wnt信号通路的具体作用靶点，探索吐根素调控Wnt信号在乳腺癌细胞迁移和浸润中的作用机制；通过本项目研究，揭示吐根素抑制Wnt信号通路、乳腺癌发生发展及转移、乳腺癌干细胞活性的作用机制，为乳腺癌的治疗提供一种潜在的新策略。本项目在执行期间内，完成了合同指标，已经申请国家专利一项，在国际一流学术期刊上发表SCI论文4篇，第一作者3篇。通讯作者1篇。一篇论文发表在国际顶级学术杂志Angewandte Chemie International Edition（第一作者JCR top 1区 影响因子：15.336）。Molecules (共同第一作者JCR2区 影响因子4.411)；Dalton Trans. (共同通讯作者JCR2区 影响因子4.390)；ONCOLOGY REPORTS（中科院JCR分区2区影响因子3.417）。