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Updated: May 24, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
AR-Q640X, a model to study the effects of constitutively active C-terminally truncated AR variants in prostate cancer
Wolfgang Streicher1, Friedemann Zengerling, Martin Laschak
1Department of Urology, Research Laboratory, University of Ulm, Prittwitzstrasse 43, 89075, Ulm, Germany.
Purpose:
A recently identified mechanism allowing prostate cancer (PCa) cells to grow in the absence of androgens is the expression of constitutively active, C-terminally truncated androgen receptor (AR) variants lacking vast parts of the ligand-binding domain. These AR variants termed ARΔLBD are either products of alternative splicing, point mutations leading to premature stop codons or proteolytic cleavage of the AR. Some controversies exist about the requirement of additional full-length AR for the full transcriptional activity of the ARΔLBD. On basis of a mutated, C-terminally truncated AR termed Q640X, we developed an experimental model for the study of ARΔLBD in PCa cells.
Methods:
Activation of AR-dependent promoters was analyzed by reporter gene assays. Dimerization studies were conducted using a mammalian two-hybrid system.
Results:
Although Q640X/Q640X homodimers were able to induce the expression of certain AR target genes, Q640X/AR heterodimers were necessary to activate the full panel of androgen-dependent genes under androgen-deprived conditions.
Conclusions:
The following study supports the hypothesis that castration-resistant prostate cancer (CRPC) cells are able to activate specific androgen-dependent genes by selective modulation of the ratio between ARΔLBD and their putative dimerization partners like the full-length AR or other ARΔLBD in the absence of androgens. The present data suggest that AR-mutant Q640X is a powerful experimental tool for the functional analysis of ARΔLBD in CRPC.
Insights
Castration-resistant prostate cancer cells can activate genes without androgens by modulating androgen receptor variants (ARΔLBD). Full activity requires heterodimers of ARΔLBD with full-length androgen receptor (AR).
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Prostate cancer (PCa) can grow without androgens via truncated androgen receptor (AR) variants (ARΔLBD).
- ARΔLBDs lack ligand-binding domains and are formed by splicing, mutations, or cleavage.
- The role of full-length AR in ARΔLBD transcriptional activity remains debated.
Purpose of the Study:
- To investigate the mechanism of ARΔLBD activity in PCa cells.
- To develop an experimental model using a mutated AR (Q640X) for studying ARΔLBD.
- To clarify the necessity of full-length AR for ARΔLBD function.
Main Methods:
- Reporter gene assays were used to measure AR-dependent promoter activation.
- A mammalian two-hybrid system was employed for dimerization studies.
Main Results:
- Q640X homodimers activated some AR target genes.
- Q640X/AR heterodimers were essential for activating the full set of androgen-dependent genes under androgen-deprived conditions.
Conclusions:
- CRPC cells can activate androgen-dependent genes by modulating ARΔLBD and full-length AR ratios without androgens.
- The Q640X mutant serves as a valuable tool for analyzing ARΔLBD function in CRPC.
