Identification of the Transcription Factor Relationships Associated with Androgen Deprivation Therapy Response and Metastatic Progression in Prostate Cancer

• Type of Material: Article
• Authors: Nitya V. Sharma, Emory University; Kathryn L. Pellegrini, Emory University; Veronique Ouellet, Centre de Recherche du Centre Hospitalier de l’Université de Montréal; Felipe O. Giuste, Emory University; Selvi Ramalingam, Emory University; Kenneth Watanabe, Emory University; Eloise Adam-Granger, Centre de Recherche du Centre Hospitalier de l’Université de Montréal; Lucresse Fossouo, Centre de Recherche du Centre Hospitalier de l’Université de Montréal; Sungyong You, Cedars-Sinai Medical Center; Sungyong Freeman, Cedars-Sinai Medical Center; Paula M Vertino, Emory University; Karen N Conneely, Emory University; Adeboye O. Osunkoya, Emory University; Dominique Trudel, Centre de Recherche du Centre Hospitalier de l’Université de Montréal; Anne-Marie Mes-Masson, Centre de Recherche du Centre Hospitalier de l’Université de Montréal; John A Petros, Emory University; Fred Saad, Centre de Recherche du Centre Hospitalier de l’Université de Montréal; Carlos S Moreno, Emory University
• Language: English
• Date: 2018-10-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2018 by the authors. Licensee MDPI, Basel, Switzerland.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/cancers10100379
• Title of Journal or Parent Work: Cancers
• ISSN: 2072-6694
• Volume: 10
• Issue: 10
• Grant/Funding Information: Research reported in this publication was supported in part by the Emory Integrated Genomics Core (EIGC) Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number UL1TR002378.; These studies were supported by the Movember Foundation GAP1 project, NIH Training Grant T32 GM008490, Winship Cancer Institute, and Emory University. F.S. is recipient of the U of M endowed Chair in Prostate Cancer. V.O., D.T., A.-M.M.-M. and F.S. are researchers of the Centre de recherche du Centre hospitalier de l’Université de Montréal which receives support from the FRQS.
• Keywords: Science & Technology; HUMAN GENOME; CARCINOMA; Oncology; prostate cancer; RESISTANCE; ENZALUTAMIDE; GENE; MECHANISMS; CELL; androgen deprivation therapy; Life Sciences & Biomedicine; transcriptional networks; RECEPTOR; metastasis; DIFFERENTIAL EXPRESSION ANALYSIS; SPLICE VARIANTS
• Research Categories: Health Sciences, Pathology; Biology, Molecular

Abstract

Background: Patients with locally advanced or recurrent prostate cancer typically undergo androgen deprivation therapy (ADT), but the benefits are often short-lived and the responses variable. ADT failure results in castration-resistant prostate cancer (CRPC), which inevitably leads to metastasis. We hypothesized that differences in tumor transcriptional programs may reflect differential responses to ADT and subsequent metastasis. Results: We performed whole transcriptome analysis of 20 patient-matched Pre-ADT biopsies and 20 Post-ADT prostatectomy specimens, and identified two subgroups of patients (high impact and low impact groups) that exhibited distinct transcriptional changes in response to ADT. We found that all patients lost the AR-dependent subtype (PCS2) transcriptional signatures. The high impact group maintained the more aggressive subtype (PCS1) signal, while the low impact group more resembled an AR-suppressed (PCS3) subtype. Computational analyses identified transcription factor coordinated groups (TFCGs) enriched in the high impact group network. Leveraging a large public dataset of over 800 metastatic and primary samples, we identified 33 TFCGs in common between the high impact group and metastatic lesions, including SOX4/FOXA2/GATA4, and a TFCG containing JUN, JUNB, JUND, FOS, FOSB, and FOSL1. The majority of metastatic TFCGs were subsets of larger TFCGs in the high impact group network, suggesting a refinement of critical TFCGs in prostate cancer progression. Conclusions: We have identified TFCGs associated with pronounced initial transcriptional response to ADT, aggressive signatures, and metastasis. Our findings suggest multiple new hypotheses that could lead to novel combination therapies to prevent the development of CRPC following ADT.