他莫昔芬（Tamoxifen，TAM）是ERα阳性乳腺癌内分泌治疗的基石，耐药是其临床应用的最大障碍。我们证实：CLC-3氯通道受ERα的调控参与雌激素促乳腺癌细胞增殖；TAM耐药的乳腺癌细胞CLC-3蛋白表达减少且分布异常。因而我们提出由于ERα表达和/或功能缺失使其调控的CLC-3蛋白表达、分布和通道活性异常，从而降低乳腺癌对TAM的敏感性。在本项目中将探讨：1）TAM抗乳腺癌作用是否经ERα调控CLC-3氯通道实现的？2）ERα和CLC-3蛋白表达、分布和通道活性的周期性是否导致TAM抗乳腺癌的周期特异性？3）ERα是否动态调控CLC-3氯通道而参与TAM耐药进程？4）结合临床病理标本和PDX模型研究ERα与ClC-3蛋白表达、通道活性和关键功能结构域，并与患者生存率的进行相关性分析，评估TAM疗效及复发。本研究将拓展TAM抗乳腺癌作用及耐药机制，为乳腺癌个性化治疗提供新的策略。

Endocrine therapy is one of the most effective targeted treatment strategies fro ER-positive breast caner. Tamoxifen (TAM) is the cornerstone of endocrine therapy. However, TAM resistance is the major obstacle in successful treatment of these breast cancer, and the molecular mechanisms underlying these processes are still fully unknown. We have demonstrated that the regulation of CLC-3 chloride channel by ERα in estrogen promoting proliferation of breast cancer cells. The expression of CLC-3 protein in TAM resistant breast cancer cells was decreased and its distribution was abnormal. Therefore, we assume that reducing the sensitivity of breast cancer to TAM attribute to the ERα expression deletion and/or gene mutations lead to the abnormal regulation of CLC-3 protein expression, subcellular distribution, and channel activity. In this project, we will explore 1) elucidae the inhibition effect of TAM on breast cancer cells through the CLC-3 chloride channel pathway which regulated by ERα? 2) Whether the periodicity of the expression, distribution and channel activity of ERα and CLC-3 protein leads to the cyclical specificity of TAM against breast cancer? 3) Whether ERα dynamically regulates the CLC-3 chloride channel, and then participates in the TAM resistance process? 4) Combine with clinical specimens, we will study the expression and heterogeneity of ERα and ClC-3 chloride channel, analyze the correlation with survival rate of breast cancer patients, so as to evaluate the efficacy and recurrence of TAM. This study will expand the mechanism of TAM against breast cancer and provide a new strategy for the individualized treatment of breast cancer.