他莫昔芬（TAM）是乳腺癌患者应用最广泛的内分泌治疗药物，但大多数患者产生耐药是其临床应用的主要障碍，TAM耐药机制和增敏药物的研究亟待突破。已有的研究表明TAM耐药细胞与敏感细胞相比有氧糖酵解水平升高，抑制有氧糖酵解是逆转TAM耐药的潜在途径。本课题组通过预实验进一步发现，可能存在GPR30/HIF-1ɑ信号通路调控TAM耐药细胞的有氧糖酵解。我们前期研究证实，黄芩素能够通过抑制GPR30信号通路的活化，发挥抗乳腺癌的效应。基于此，本项目将考察黄芩素在体内外逆转TAM耐药的药理学活性，并研究黄芩素对耐药细胞有氧糖酵解，以及对GPR30和HIF-1ɑ表达、分布、活性的影响，阐明黄芩素通过抑制GPR30/HIF-1ɑ信号通路下调有氧糖酵解，逆转TAM耐药的作用机制。本项目延续前期研究，为深入探索黄芩素抗乳腺癌的作用环节和机制提供新依据，也为TAM耐药增敏剂的研究提供新靶点和新思路。

Tamoxifen is the most frequently used endocrine agent for treatment of breast cancer patients, but most patients obtain resistance which is the major obstacle for its clinical use. Understanding the mechanisms of tamoxifen resistance and devising sensitizer to overcome drug resistance are urgent tasks. Accumulated evidences indicated that tamoxifen-resistant cells display increased aerobic glycolysis compared with sensitive cells, and inhibition of aerobic glycolysis restores tamoxifen sensitivity in resistant breast cancer cells. In addition, our preliminary experiment results showed that G protein-coupled receptor 30 (GPR30)/hypoxia-inducible factor-1α (HIF-1ɑ) signaling pathway may regulate aerobic glycolysis of tamoxifen-resistant cells. We previously confirmed that baicalein has potent anti-breast cancer activity, meanwhile it possesses inhibitory effect on GPR30 signaling pathway activation. In this study, we will evaluate the effects of baicalein on increasing tamoxifen sensitivity in vitro and in vivo. Meanwhile, we will detect whether baicalein could take effect on aerobic glycolysis of tamoxifen-resistant cells, and the expression, subcellular distribution, activity of GPR30 and HIF-1ɑ, to explore the mechanism that baicalein reverses tamoxifen resistance via down regulation of aerobic glycolysis by inhibiting GPR30/HIF-1ɑ signaling pathway. In general, this project may provide new evidence for the activity and mechanism of baicalein in breast cancer treatment. Furthermore, it may offer a new target and a strategy for discovering sensitizer to overcome tamoxifen resistance.