BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: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. CONCLUSIONS: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.
Authors: Robert Szulkin; Thomas Whitington; Martin Eklund; Markus Aly; Rosalind A Eeles; Douglas Easton; Z Sofia Kote-Jarai; Ali Amin Al Olama; Sara Benlloch; Kenneth Muir; Graham G Giles; Melissa C Southey; Liesel M Fitzgerald; Brian E Henderson; Fredrick Schumacher; Christopher A Haiman; Johanna Schleutker; Tiina Wahlfors; Teuvo L J Tammela; Børge G Nordestgaard; Tim J Key; Ruth C Travis; David E Neal; Jenny L Donovan; Freddie C Hamdy; Paul Pharoah; Nora Pashayan; Kay-Tee Khaw; Janet L Stanford; Stephen N Thibodeau; Shannon K McDonnell; Daniel J Schaid; Christiane Maier; Walther Vogel; Manuel Luedeke; Kathleen Herkommer; Adam S Kibel; Cezary Cybulski; Jan Lubiński; Wojciech Kluźniak; Lisa Cannon-Albright; Hermann Brenner; Katja Butterbach; Christa Stegmaier; Jong Y Park; Thomas Sellers; Hui-Yi Lin; Hui-Yi Lim; Chavdar Slavov; Radka Kaneva; Vanio Mitev; Jyotsna Batra; Judith A Clements; Amanda Spurdle; Manuel R Teixeira; Paula Paulo; Sofia Maia; Hardev Pandha; Agnieszka Michael; Andrzej Kierzek; Henrik Gronberg; Fredrik Wiklund Journal: Prostate Date: 2015-07-14 Impact factor: 4.104
Authors: D Andrew Loblaw; Katherine S Virgo; Robert Nam; Mark R Somerfield; Edgar Ben-Josef; David S Mendelson; Richard Middleton; Stewart A Sharp; Thomas J Smith; James Talcott; Maryellen Taplin; Nicholas J Vogelzang; James L Wade; Charles L Bennett; Howard I Scher Journal: J Clin Oncol Date: 2007-04-02 Impact factor: 44.544
Authors: Jonathan E McDunn; Zhen Li; Klaus-Peter Adam; Bruce P Neri; Robert L Wolfert; Michael V Milburn; Yair Lotan; Thomas M Wheeler Journal: Prostate Date: 2013-07-03 Impact factor: 4.104
Authors: Dinesh Singh; Phillip G Febbo; Kenneth Ross; Donald G Jackson; Judith Manola; Christine Ladd; Pablo Tamayo; Andrew A Renshaw; Anthony V D'Amico; Jerome P Richie; Eric S Lander; Massimo Loda; Philip W Kantoff; Todd R Golub; William R Sellers Journal: Cancer Cell Date: 2002-03 Impact factor: 31.743
Authors: Leander Van Neste; Alan W Partin; Grant D Stewart; Jonathan I Epstein; David J Harrison; Wim Van Criekinge Journal: Prostate Date: 2016-04-28 Impact factor: 4.104