虚、瘀、毒是乳腺癌的病机要点，基于益气活血解毒法的固本抑瘤II号(GY)是肿瘤专家郁仁存教授多年经验总结创制的代表方药，具有良好的临床疗效。肝素酶(HPSE)切割底物硫酸肝素(HS)，影响其结构和功能，进而影响多种下游信号转导。基于高HPSE水平的微环境中自噬(AP)增多、细胞死亡减少而促进肿瘤转移的最新研究发现，分析我们前期证实的GY对AP的双向调节作用、对HPSE的抑制作用，我们提出假说：作为HPSE的唯一底物，HS结构的变化是开启自噬-存活/自噬-死亡的关键；GY通过干预HS结构，影响HPSE及AP信号转导，抑制乳腺癌转移。本研究以不同HPSE水平小鼠/细胞为研究工具，从肝素酶-硫酸肝素-自噬角度探讨“益气活血解毒”法单独应用及与西药联合应用的作用及机理，诠释其抗肿瘤作用的新内涵，为临床更好应用该中药提供理论指导和实验数据支持。

BACKGROUND: YIQIHUOXUEJIEDU is one of the successful principles for TCM treatment on tumor, which is widely used for kinds of tumor clinic treatment, and has been proved to can reduce tumor proliferation and metastasis, alleviate side-effects of chemotherapy/radiotherapy. GUBUYILIU II (GY) is the typical prescription based on this principle. Heparanase and heparan sulfate have recently been reported to be new targets for cancer therapy, as heparanase often is expressed at high levels in malignant tumors. Autophagy, which is constitutively executed at basal level in all cells, promotes cellular homeostasis by regulating organelles and proteins turnover. In tumor cells, autophagy is activated in response to various cellular stresses, including nutrient and growth factor starvation, as well as hypoxia. It is now well established that autophagy can act as tumor suppressor and tumor promoter. The different roles of autophagy in cancer cells seem to depend on tumor type, stage, and genetic context. Recently it is reported that heparanase enhances tumor growth and chemoresistance by promoting autophagy. Since GY is found to reduce tumor proliferation and metastasis by inhibit heparanase expression, and autophagy is one of the target of GY on breast cancer, we come to our hypothesis that by heparanase sulfate structure modification, heparanase promote autophagy, and GY reduce tumor proliferation and metastasis by heparanase, heparan sulfate, and autophagy.. OBJECTIVE: To investigate the anti-tumor activity of active component alignments isolated from the prescription GY on both mice models and breast cancer cells models (heparanase transgenic mice/cells and wide type mice/cells), to investigate its effects on heparanase, heparan sulfate, and autophagy in vitro and in vivo.. EXPECTED RESULTS: The aim of this project is to make clear of GY mechanisms on breast cancer metastasis, expecially by its effects on heparanase, heparan sulfate, and autophagy. The expected result of this project is to provide a new therapeutic strategy. Articles published in journals and patents will be the direct results of this project.