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Correspondence: cmoreno@emory.edu; Tel.: +1-404-712-2809

Author Contributions: Conceptualization, J.A.P. and C.S.M.; Data curation, N.V.S., K.L.P., V.O., F.O.G., S.R., K.W., E.A.-G., L.F., S.Y., M.R.F., A.O.O., D.T. and A.-M.M.-M.; Formal analysis, N.V.S., K.L.P., F.O.G., S.R., K.W., S.Y., K.C. and C.S.M.; Funding acquisition, C.S.M.; Investigation, N.V.S., K.L.P., V.O., F.O.G., P.V., K.C., A.O.O., D.T. and A.-M.M.-M.; Project administration, J.A.P., F.S. and C.S.M.; Resources, S.Y., M.R.F., D.T., A.-M.M.-M., J.A.P. and F.S.; Software, K.W.; Supervision, P.V., K.C., D.T., A.-M.M.-M., J.A.P., F.S. and C.S.M.; Visualization, N.V.S.; Writing—original draft, N.V.S.; Writing—review & editing, N.V.S., K.L.P., V.O., F.O.G., S.R., K.W., E.A.-G., L.F., S.Y., M.R.F., P.V., K.C., A.O.O., D.T., A.-M.M.-M., J.A.P., F.S. and C.S.M.

We would like to thank patients that consented to participate into the CRCHUM prostate cancer biobank and personal from the biobank.

We are grateful to Andrée-Anne Grosset for her assistance in reviewing the cases and Nathalie Delvoye for clinical data collection.

Biobanking was done in collaboration with the Réseau de Recherche sur le cancer of the Fonds de Reserche Québec-Santé (FRQS) that is affiliated with the Canadian Tumor Repository Network (CTRNet).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflicts of Interest: The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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Research Funding:

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.

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.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • androgen deprivation therapy
  • prostate cancer
  • transcriptional networks
  • metastasis
  • DIFFERENTIAL EXPRESSION ANALYSIS
  • SPLICE VARIANTS
  • HUMAN GENOME
  • RECEPTOR
  • RESISTANCE
  • GENE
  • CELL
  • CARCINOMA
  • MECHANISMS
  • ENZALUTAMIDE

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

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Journal Title:

Cancers

Volume:

Volume 10, Number 10

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Article | Final Publisher PDF

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.

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© 2018 by the authors. Licensee MDPI, Basel, Switzerland.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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