Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA.
Mol Syst Biol. 2018 Aug 14;14(8):e8202. doi: 10.15252/msb.20188202.
Identifying critical pathways governing disease progression is essential for accurate prognosis and effective therapy. We developed a broadly applicable and novel systems-level gene discovery strategy. This approach focused on constitutively active androgen receptor (AR) splice variant-driven pathways as representative of an intractable mechanism of prostate cancer (PC) therapeutic resistance. We performed a meta-analysis of human prostate samples using weighted gene co-expression network analysis combined with experimental AR variant transcriptome analyses. An AR variant-driven gene module that is upregulated during human PC progression was identified. We filtered this module by identifying genes that functionally interacted with AR variants using a high-throughput synthetic genetic array screen in This strategy identified seven AR variant-regulated genes that also enhance AR activity and drive cancer progression. Expression of the seven genes predicted poor disease-free survival in large independent PC patient cohorts. Pharmacologic inhibition of interacting members of the gene set potently and synergistically decreased PC cell proliferation. This unbiased and novel gene discovery strategy identified a clinically relevant, oncogenic, interacting gene hub with strong prognostic and therapeutic potential in PC.
确定控制疾病进展的关键途径对于准确的预后和有效的治疗至关重要。我们开发了一种广泛适用且新颖的系统水平基因发现策略。该方法侧重于持续激活的雄激素受体 (AR) 剪接变体驱动的途径，以代表前列腺癌 (PC) 治疗耐药的一种棘手机制。我们使用加权基因共表达网络分析结合实验 AR 变体转录组分析对人类前列腺样本进行了荟萃分析。确定了在人类 PC 进展过程中上调的 AR 变体驱动的基因模块。我们通过使用高通量合成遗传阵列筛选鉴定与 AR 变体相互作用的基因来筛选该模块。该策略鉴定了七个调节 AR 变体的基因，这些基因也增强了 AR 活性并驱动癌症进展。这七个基因的表达预测了大型独立 PC 患者队列中无病生存不良。该基因集相互作用成员的药理学抑制强烈且协同地降低了 PC 细胞的增殖。这种无偏且新颖的基因发现策略确定了一个具有临床相关性、致癌性、相互作用的基因枢纽，在 PC 中具有强大的预后和治疗潜力。
