花生四烯酸（AA）显著提高乳腺癌的发生率。除了环氧化酶和脂氧合酶调控的两条代谢通路外，AA还有第三条代谢通路经细胞色素P450（CYP）酶生成羟基花生四烯酸（HETEs）和环氧花生四烯酸（EETs）。靶向CYP通路既能杀伤肿瘤细胞，同时也抑制肿瘤周围的间质微环境，因此在乳腺癌的防治中具有重要的潜在应用前景。我们先前的研究发现葫芦素E(CuE)是潜在的治疗乳腺癌及其转移的新药物。然而，CuE是否靶向AA的CYP代谢通路以及对CYP酶的作用机理未见报道。本项目拟通过细胞和动物模型，结合临床样本，系统研究CuE对AA的CYP代谢通路以及CYP酶的作用机制。本项目的实施不仅确定CuE通过AA代谢通路防治乳腺癌及对CYP酶的作用机理；还揭示AA、CYP、EETs和HETEs与乳腺癌之间的联系，为乳腺癌的发病机制提供新的内容，并对其治疗提供新的策略。

Arachidonic acid (AA) can significantly increase the incidence of breast cancer. Among the AA metabolites, the prostaglandins and leukotrienes are the best known. They are generated by two pathways controlled by the enzyme systems cyclooxygenase and lipoxygenase, respectively. However, AA is also substrate for a third enzymatic pathway, the cytochrome P450 (CYP) system. This third eicosanoid pathway consists of two main branches: ω-hydroxylases convert arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases convert it to epoxyeicosatrienoic acids (EETs). These lipid autacoids may be involved in cancer in a few different ways: either in cell-autonomous tumor survival and growth or in modulating stromal processes, such as angiogenesis and inflammation that can support tumor progression. The EETs and HETEs pathways should be evaluated as potential targets in cancer therapy, directed both against tumor cells and their surrounding stroma. Cucurbitacin E (CuE) has significant anti-tumor activity, and is a potential candidate as new anti-tumor herbal medicines. Previous our studies found CuE inhibits tumor angiogenesis through VEGFR2 mediated Jak2/STAT3 signaling pathway and inhibits breast tumor metastasis by suppressing cell migration and invasion. Further studies in this project will investigate the effects of CuE on the pathway of CYP-derived AA in the breast cancer and the CYP isoforms activities. Moreover, the project will reveal the relationship of AA, CYP, HETEs and EETs in breast cancer, and provide novel mechanisms for the pathogenesis of breast cancer and evidence for development new strategy for breast cancer treatment. Furthermore, CYP-associated CuE metabolic studies not only are one of the major attritions in drug development, but also are considered cost-effective for predicting the potential drug-drug interaction in the clinic.