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Updated: Jan 21, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
07:25

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

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Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate

Mark P Labrecque1, Ilsa M Coleman2,3, Lisha G Brown1

  • 1Department of Urology, University of Washington, Seattle, Washington, USA.

The Journal of Clinical Investigation
|July 31, 2019
PubMed

Insights

Metastatic castration-resistant prostate cancer (mCRPC) exhibits five distinct phenotypes based on androgen receptor (AR) and neuroendocrine (NE) gene expression. Understanding these AR and RE1-silencing transcription factor (REST) driven classifications is key for future prostate cancer treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Metastatic castration-resistant prostate cancer (mCRPC) is a complex disease characterized by heterogeneity in disease progression and therapeutic resistance.
  • Understanding the molecular drivers of mCRPC is crucial for developing effective treatment strategies.

Purpose of the Study:

  • To deeply phenotype mCRPC metastases and patient-derived xenograft (PDX) lines.
  • To identify distinct molecular subtypes of mCRPC based on gene expression profiles.
  • To elucidate the roles of androgen receptor (AR) and RE1-silencing transcription factor (REST) in mCRPC phenotypes.

Main Methods:

  • Whole genome RNA sequencing of mCRPC metastases and PDX lines.
  • Gene set enrichment analysis to identify molecular pathways.
  • Immunohistochemistry to validate protein expression.
  • REST knockdown experiments in cell lines.

Main Results:

  • Five mCRPC phenotypes were identified: AR-high (ARPC), AR-low (ARLPC), amphicrine (AMPC), double-negative (DNPC), and small cell/neuroendocrine (SCNPC).
  • Loss of RE1-silencing transcription factor (REST) activity was observed in AMPC and SCNPC PDX models.
  • Attenuated REST activity drives the AMPC phenotype, but is insufficient for SCNPC conversion.
  • A 26-gene signature was developed to distinguish the five mCRPC phenotypes, including a squamous differentiation subtype within DNPC.

Conclusions:

  • Androgen receptor (AR) and RE1-silencing transcription factor (REST) play central roles in classifying treatment-resistant mCRPC phenotypes.
  • Molecular classification of mCRPC subtypes can potentially guide future therapeutic studies and clinical trial design.
  • Identification of distinct mCRPC phenotypes offers new avenues for targeted therapies.
Keywords:
Cell BiologyExpression profilingMolecular pathologyOncologyProstate cancer

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