Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
Cancer Cell. 2019 Mar 18;35(3):401-413.e6. doi: 10.1016/j.ccell.2019.01.008. Epub 2019 Feb 14.
Androgen deprivation therapy for prostate cancer (PCa) benefits patients with early disease, but becomes ineffective as PCa progresses to a castration-resistant state (CRPC). Initially CRPC remains dependent on androgen receptor (AR) signaling, often through increased expression of full-length AR (ARfl) or expression of dominantly active splice variants such as ARv7. We show in ARv7-dependent CRPC models that ARv7 binds together with ARfl to repress transcription of a set of growth-suppressive genes. Expression of the ARv7-repressed targets and ARv7 protein expression are negatively correlated and predicts for outcome in PCa patients. Our results provide insights into the role of ARv7 in CRPC and define a set of potential biomarkers for tumors dependent on ARv7.
用于治疗前列腺癌 (PCa) 的雄激素剥夺疗法对早期疾病患者有益，但随着 PCa 发展为去势抵抗性状态 (CRPC)，该疗法变得无效。最初，CRPC 仍然依赖于雄激素受体 (AR) 信号，通常通过全长 AR (ARfl) 的表达增加或表达显性激活的剪接变体（如 ARv7）。我们在依赖 ARv7 的 CRPC 模型中表明，ARv7 与 ARfl 结合在一起，抑制一组生长抑制基因的转录。ARv7 抑制靶基因的表达和 ARv7 蛋白表达呈负相关，并可预测 PCa 患者的预后。我们的研究结果为 ARv7 在 CRPC 中的作用提供了深入的了解，并为依赖 ARv7 的肿瘤定义了一组潜在的生物标志物。
