雌激素受体调节剂他莫昔芬（Tamoxifen，Tam）是应用最广泛的乳腺癌内分泌治疗药物，但Tam耐药性的产生与乳腺癌的复发是临床面临的重大挑战。SIRT3是一种重要的线粒体去乙酰化酶，通过去乙酰化多种线粒体蛋白参与肿瘤发生发展。我们首次发现SIRT3在Tam耐药的乳腺癌细胞中表达异常增高，并在Tam耐药调控中发挥重要作用。但SIRT3促进Tam耐药的具体机制尚不清楚。本研究拟在前期工作基础上，深入研究SIRT3在线粒体直接结合雌激素受体ERβ，去ERβ(K4)乙酰化修饰，降低线粒体ERβ蛋白的稳定性，进而促进Tam耐药的作用机制；并进一步通过干预SIRT3评估其作为临床逆转Tam耐药新靶点的可能性和重要意义。

Tamoxifen, a selective estrogen receptor antagonist, is the most commonly used endocrine therapy in treatment of breast cancer. Tamoxifen resistance and tumor recurrence are the major obstacle to successful treatment of breast cancer. SIRT3, a mitochondrial deacetylase, plays a critical role in the regulation of cancer progression through deacetylating mitochondrial proteins. We recently reported that the mitochondrial protein deacetylase SIRT3 was significantly up-regulated in tamoxifen-resistant breast cancer cells and was involved in the regulation of tamoxifen sensitivity; yet, the mechanism and clinical significance of SIRT3 in tamoxifen resistance remain unclear. In this grant application, we propose to investigate the molecular mechanism by which SIRT3 regulates tamoxifen resistance in breast cancer. We hypothesize that SIRT3 reduces ERβ protein stability through deacetylating this estrogen receptor. The proposed studies may not only uncover a new molecular mechanism of tamoxifen resistance, but also lead to a novel approach to effective reversing Tam resistance through intervention of SIRT3.