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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
06:48

An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Published on: September 18, 2013

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Identification of an oncogenic network with prognostic and therapeutic value in prostate cancer

Fiorella Magani1,2, Eric R Bray3, Maria J Martinez2

  • 1Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.

Molecular Systems Biology
|August 16, 2018
PubMed

Insights

Researchers discovered a novel gene network driving prostate cancer (PC) progression and therapeutic resistance. This finding offers new targets for improving PC prognosis and treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Systems Biology

Background:

  • Identifying key pathways is crucial for prostate cancer (PC) prognosis and therapy.
  • Therapeutic resistance in PC is often driven by constitutively active androgen receptor (AR) splice variants.
  • Novel strategies are needed to uncover genes involved in AR variant-driven resistance.

Purpose of the Study:

  • To develop a systems-level gene discovery strategy to identify critical pathways in PC.
  • To uncover AR variant-driven genes that contribute to PC progression and therapeutic resistance.
  • To identify potential prognostic and therapeutic targets for prostate cancer.

Main Methods:

  • Meta-analysis of human prostate samples using weighted gene co-expression network analysis.
  • Experimental AR variant transcriptome analyses.
  • High-throughput synthetic genetic array screen in *Schizosaccharomyces pombe* to identify functional interactions with AR variants.

Main Results:

  • Identified an AR variant-driven gene module upregulated during PC progression.
  • Discovered seven AR variant-regulated genes that enhance AR activity and promote cancer progression.
  • These seven genes predicted poor disease-free survival in independent PC patient cohorts.
  • Pharmacologic inhibition of interacting genes synergistically decreased PC cell proliferation.

Conclusions:

  • A novel, unbiased gene discovery strategy identified a clinically relevant gene hub in PC.
  • This gene hub is oncogenic, has strong prognostic potential, and offers therapeutic opportunities.
  • Targeting this AR variant-regulated gene network may overcome therapeutic resistance in prostate cancer.
Keywords:
androgen receptor splice variantscastration resistancemitotic gene signatureweighted gene co‐expression network analysisyeast synthetic genetic array

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