Iorns Elizabeth, Turner Nicholas C, Elliott Richard, Syed Nelofer, Garrone Ornella, Gasco Milena, Tutt Andrew N J, Crook Tim, Lord Christopher J, Ashworth Alan
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
Cancer Cell. 2008 Feb;13(2):91-104. doi: 10.1016/j.ccr.2008.01.001.
Therapies that target estrogen signaling have transformed the treatment of breast cancer. However, the effectiveness of these agents is limited by the development of resistance. Here, an RNAi screen was used to identify modifiers of tamoxifen sensitivity. We demonstrate that CDK10 is an important determinant of resistance to endocrine therapies and show that CDK10 silencing increases ETS2-driven transcription of c-RAF, resulting in MAPK pathway activation and loss of tumor cell reliance upon estrogen signaling. Patients with ER alpha-positive tumors that express low levels of CDK10 relapse early on tamoxifen, demonstrating the clinical significance of these observations. The association of low levels of CDK10 with methylation of the CDK10 promoter suggests a mechanism by which CDK10 expression is reduced in tumors.
靶向雌激素信号传导的疗法已经改变了乳腺癌的治疗方式。然而，这些药物的有效性受到耐药性发展的限制。在此，我们利用RNA干扰筛选来鉴定他莫昔芬敏感性的调节因子。我们证明，细胞周期蛋白依赖性激酶10（CDK10）是内分泌治疗耐药性的一个重要决定因素，并表明CDK10沉默会增加ETS2驱动的c-RAF转录，导致丝裂原活化蛋白激酶（MAPK）途径激活以及肿瘤细胞对雌激素信号传导的依赖性丧失。雌激素受体α（ERα）阳性肿瘤且CDK10表达水平低的患者，他莫昔芬治疗后早期复发，证明了这些观察结果的临床意义。CDK10低水平与CDK10启动子甲基化之间的关联提示了肿瘤中CDK10表达降低的一种机制。
