SIRT3 促进乳腺癌细胞Tamoxifen耐药机制及其临床意义的研究

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.

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。

他莫昔芬（Tamoxifen，Tam）是雌激素受体调节剂，也是应用最广泛的乳腺癌内分泌治疗药物。但临床面临的问题是接受 Tamoxifen 治疗的肿瘤患者，尽管早期治疗反应非常好，但大多肿瘤细胞对此药物产生获得性抵抗，导致肿瘤复发，这些都是临床面临的重大挑战。Sirtuins 家族是一类高度保守的，依赖于 NAD+的去乙酰化酶，可参与调控细胞代谢、应激、DNA 修复、凋亡等多种生物过程。SIRT3是Sirtuins 家族的一员，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。我们的研究发现SIRT3在Tamoxifen耐药的乳腺癌细胞中表达异常增高，并在Tamoxifen耐药调控中发挥重要作用。本课题我们深入研究发现SIRT3可以直接结合ERβ并调控ERβ的表达，证实了SIRT3通过控制雌激素受体ERβ，进而促进Tamoxifen耐药的作用机制，我们还需要通过干预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。