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Modeling truncated AR expression in a natural androgen responsive environment and identification of RHOB as a direct

Hui-Chi Tsai1, David L Boucher, Anthony Martinez

  • 1Department of Biochemistry & Molecular Medicine, School of Medicine and Cancer Center, University of California Davis, Davis, CA, USA.

Plos One
|December 5, 2012
PubMed

Insights

Truncated androgen receptor (TC-AR) drives androgen-independent prostate cancer growth by activating target genes without DHT. This study models TC-AR

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Endocrinology

Background:

  • Prostate cancer (PCa) progression to androgen-independent (ADI) growth is linked to androgen receptor (AR) alterations.
  • Putative truncated AR isoforms with ligand-independent activity are implicated in ADI PCa.
  • Understanding the specific roles of full-length AR (FL-AR) versus truncated AR (TC-AR) is crucial for therapeutic strategies.

Purpose of the Study:

  • To establish and utilize a novel inducible model system to compare the functions of TC-AR and FL-AR in prostate cancer cells.
  • To investigate the ability of TC-AR to confer androgen-independent growth in an androgen-dependent cell line.
  • To identify distinct transcriptional targets regulated by TC-AR compared to FL-AR.

Main Methods:

  • Development of an inducible expression system for a C-terminally truncated AR (TC-AR) in LNCaP cells.
  • Analysis of AR nuclear translocation, transcriptional activity, and target gene regulation in the presence and absence of dihydrotestosterone (DHT).
  • Comparison of gene expression profiles regulated by FL-AR and TC-AR, including investigation of specific TC-AR-regulated genes like RHOB.

Main Results:

  • Overexpression of TC-AR led to the downmodulation of endogenous FL-AR, allowing for a direct comparison of their functions.
  • TC-AR translocated to the nucleus, activated AR target genes independently of DHT, and was sufficient to drive androgen-independent growth in LNCaP cells.
  • Distinct sets of target genes were regulated by FL-AR and TC-AR, with RHOB identified as a key gene uniquely activated by TC-AR.

Conclusions:

  • TC-AR can independently drive prostate cancer cell growth and migration, contributing to androgen-independent progression.
  • RHOB, uniquely regulated by TC-AR, plays a role in the observed morphological changes and increased migration in TC-AR expressing cells.
  • This study provides a valuable model for dissecting the distinct roles of AR isoforms in prostate cancer, highlighting TC-AR as a potential therapeutic target.

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