TOP2A and EZH2 provide early detection of an aggressive prostate cancer subgroup

David P. Labbé, Christopher J. Sweeney, Myles Brown, Phillip Galbo, Spencer Rosario, Kristine M. Wadosky, Sheng Yu Ku, Martin Sjöström, Mohammed Alshalalfa, Nicholas Erho, Elai Davicioni, R. Jeffrey Karnes, Edward M. Schaeffer, Robert B. Jenkins, Robert B. Den, Ashley E. Ross, Michaela Bowden, Ying Huang, Kathryn P. Gray, Felix Y. FengDaniel E. Spratt, David W. Goodrich, Kevin H. Eng, Leigh Ellis

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches.

Original languageEnglish (US)
Pages (from-to)7072-7083
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number22
DOIs
StatePublished - Nov 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Labbé, D. P., Sweeney, C. J., Brown, M., Galbo, P., Rosario, S., Wadosky, K. M., Ku, S. Y., Sjöström, M., Alshalalfa, M., Erho, N., Davicioni, E., Karnes, R. J., Schaeffer, E. M., Jenkins, R. B., Den, R. B., Ross, A. E., Bowden, M., Huang, Y., Gray, K. P., ... Ellis, L. (2017). TOP2A and EZH2 provide early detection of an aggressive prostate cancer subgroup. Clinical Cancer Research, 23(22), 7072-7083. https://doi.org/10.1158/1078-0432.CCR-17-0413