益气活血解毒是针对肿瘤虚瘀毒证候要点的重要治疗法则，固本抑瘤II号是郁仁存多年经验总结的该法则有效代表方药。前期研究发现该方抑制乳腺癌细胞增殖、转移与mTOR通路细胞自噬、caspase途径凋亡有关；而mTOR和caspase通路都受肝素酶(Hpa)、硫酸肝素(HS)及HS-FGF-FGFR信号转导复合体调控。肿瘤细胞Hpa表达增高，引起HS结构变化，有利于HS-FGF-FGFR形成，促进肿瘤细胞增殖、转移。因此我们推测该方抗肿瘤作用与Hpa、HS及 HS-FGF-FGFR有关。本课题以全方及其益气、活血、解毒组分为工具，以不同Hpa/HS水平的小鼠乳腺癌移植瘤和癌细胞株为研究对象，研究不同治则中药是否通过影响①Hpa；②HS；③HS-FGF-FGFR而干预乳腺癌细胞自噬/凋亡性死亡，抑制肿瘤生长、转移；从肿瘤微环境角度诠释益气活血解毒法组方配伍科学原理。

BACKGROUND: GUBUYILIU is one of the successful prescription based on YIQIHUOXUEJIEDU principle for tumor treatment in China. Glycans including glycosaminoglycans (GAGs), from Traditional Chinese Medicine (TCM), were widely used for kinds of tumor clinic treatment, and have been proved to can inhibit tumor proliferation and metastasis, alleviate side-effects of chemotherapy/radiotherapy. Some polysaccharides are found to be mimetics of GAGs. Heparanase and heparan sulfate have recently been reported to be new targets for cancer therapy, as heparanase often is expressed at high levels in the tumors. This project is based on the results of preliminary studies that we have found certain TCM can inhibit tumor growth in clinic, animal and cellular models. We are particularly interested in polysaccharides, extracted from the typical prescription (GUBENYILIU) of Beijing Hospital of Traditional Chinese Medicine. These extracts can be regarded as extrinsic GAGs. We postulate that some active components from GUBENYILIU can modulate the activity, expression, and structure of endogenous heparan sulfate, by thus change heparanase activity and FGF signal passthway. OBJECTIVE: To investigate the anti-tumor activity of active component alignments isolated from the prescription by different heparanase level mouse breast tumor transplantation models and cell lines (4T1,MCF7,MAB231), to investigate its mechanisms of inhibiting tumor proliferation and metastasis, to explore the extrinsic TCM on endogenous heparan sulfate and heparanase activity and expression, to explore FGF and cell death-apoptosis and autophagy in breast tumor. EXPECTED RESULTS: The aim of this project is to compare the different components based on different treatment principle,to find the most active components or compound from some TCM, and to make clear of its mechanisms, expecially by its effects on endogeous heparan sulfate and heparanase. The expected result of this project is to provide a new therapeutic strategy or preclinical component from herbal medicine for breast tumor. Articles published in journals and patents will be the direct results of this project.