Department of Oncology and Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
Prostate. 2020 Feb;80(2):198-208. doi: 10.1002/pros.23932. Epub 2019 Dec 3.
Both hormone-sensitive and castration- and enzalutamide-resistant prostate cancers (PCa) depend on the ternary complex factor (TCF) protein ELK1 to serve as a tethering protein for the androgen receptor (AR) to activate a critical set of growth genes. The two sites in ELK1 required for AR binding are conserved in other members of the TCF subfamily, ELK3 and ELK4. Here we examine the potential utility of the three proteins as prognosticators of disease recurrence in PCa.
Transcriptional activity assays; Retrospective analysis of PCa recurrence using data on 501 patients in The Cancer Genome Atlas (TCGA) database; Unpaired Wilcoxon rank-sum test and multiple comparison correction using the Holm's method; Spearman's correlations; Kaplan-Meier methods; Univariable and multivariable Cox regression analyses; LASSO-based penalized Cox regression models; Time-dependent area under the receiver operating characteristic (ROC) curve.
ELK4 but not ELK3 was coactivated by AR similar to ELK1. Tumor expression of neither ELK3 nor ELK4 was associated with disease-free survival (DFS). ELK1 was associated with higher clinical T-stage, pathology T-stage, Gleason score, prognostic grade, and positive lymph node status. ELK1 was a negative prognosticator of DFS, independent of ELK3, ELK4, clinical T-stage, pathology T-stage, prognostic grade, lymph node status, age, and race. Inclusion of ELK1 increased the abilities of the Oncotype DX and Prolaris gene panels to predict disease recurrence, correctly predicting disease recurrence in a unique subset of patients.
ELK1 is a strong, independent prognosticator of disease recurrence in PCa, underscoring its unique role in PCa growth. Inclusion of ELK1 may enhance the utility of currently used prognosticators for clinical decision making in prostate cancer.
激素敏感型和去势及恩杂鲁胺耐药的前列腺癌（PCa）均依赖于三元复合物因子（TCF）蛋白 ELK1 作为雄激素受体（AR）的连接蛋白，以激活一组关键的生长基因。ELK1 中 AR 结合所需的两个位点在 TCF 亚家族的其他成员 ELK3 和 ELK4 中是保守的。在这里，我们研究了这三种蛋白质作为 PCa 疾病复发的预后标志物的潜在效用。
转录活性测定；使用来自癌症基因组图谱（TCGA）数据库的 501 名患者的数据进行 PCa 复发的回顾性分析；使用 Holm 方法进行非配对 Wilcoxon 秩和检验和多重比较校正；Spearman 相关性；Kaplan-Meier 方法；单变量和多变量 Cox 回归分析；基于 LASSO 的惩罚 Cox 回归模型；时间依赖性接收者操作特征（ROC）曲线下面积。
AR 类似地与 ELK4 共同激活，但与 ELK3 不同。ELK3 或 ELK4 的肿瘤表达与无病生存期（DFS）无关。ELK1 与较高的临床 T 分期、病理 T 分期、Gleason 评分、预后分级和阳性淋巴结状态相关。ELK1 是 DFS 的负面预后因素，独立于 ELK3、ELK4、临床 T 分期、病理 T 分期、预后分级、淋巴结状态、年龄和种族。纳入 ELK1 增加了 Oncotype DX 和 Prolaris 基因面板预测疾病复发的能力，正确预测了一组独特的患者的疾病复发。
ELK1 是 PCa 疾病复发的强有力的独立预后因素，突出了其在 PCa 生长中的独特作用。纳入 ELK1 可能会增强目前用于前列腺癌临床决策的预后标志物的实用性。
