乳腺癌细胞与肿瘤微环境免疫细胞的交互作用是促进肿瘤发生衍进的关键因素，其中乳腺癌细胞内源基因的异常表达对肿瘤免疫微环境重塑至关重要。到目前为止，有关EMT转录因子Zeb1异常表达对肿瘤免疫微环境的影响鲜有报道。我们前期通过构建Zeb1基因纯合敲除的乳腺癌小鼠模型等实验发现，乳腺癌细胞中异常活化的Zeb1/IL-8 signaling以旁分泌方式募集并诱导M2型TAMs极化，进而促进乳腺癌恶性进展。本项目拟在此基础上，（1）深入阐明Zeb1/IL-8 signaling调控M2型TAMs极化及重塑乳腺癌免疫微环境的病理机制；（2）分析乳腺癌临床病例中Zeb1与IL-8表达的相关性，及其对M2型TAMs极化和促癌作用的影响；（3）利用乳腺癌动物模型，研究Zeb1/IL-8 signaling调控乳腺癌免疫微环境功能和肿瘤恶性进展的在体作用，为后续开发靶向治疗策略提供理论依据和技术支持。

The crosstalk between breast cancer cells and their tumor immune microenvironment is critical for tumor progression. It has been demonstrated that the endogenous gene regulation in breast cancer cells plays pivotal roles in the remodeling of tumor immune microenvironment. The zinc finger E-box binding homeobox 1 (Zeb1), as a master transcriptional factor of EMT, promotes breast cancer development, therapeutic resistance and distant metastasis through genetic and epigenetic mechanisms. However, the potential roles of ectopic Zeb1 in the regulation of tumor immune microenvironment remain largely unknown. To do so, we crossed the floxed Zeb1 allele homozygously into PyMT mice to generate PyMT;Zeb1cKO (MMTV-Cre;PyMT;Zeb1fl/fl) mice. Our preliminary data indicated that breast cancer-derived Zeb1/IL-8 signaling induces TAM (tumor-associated macrophage) polarization to a M2 phenotype and thus drives tumorigenesis in a paracrine action. Consequently, this project is proposed (1) to study the molecular mechanism by which Zeb1 regulates IL-8 expression, demonstrating the relationship between these factors and the tumor immune microenvironment remodeling; (2) to elucidate the correlation between Zeb1 and IL-8 expression in clinical patients of breast cancer; (3) to investigate the in vivo function of Zeb1/IL-8 cascade in the regulation of tumor immune microenvironment and breast cancer pathogenesis using transgenic mouse models. This project will help to reveal the relationship between Zeb1 and IL-8 in the development and progression of breast cancer, especially providing a novel strategy for the individualized prevention and treatment of the disease.