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Updated: Jun 30, 2026
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 19, 2013
Androgen receptor variants and prostate cancer in humanized AR mice
Diane M Robins1, Megan A Albertelli, Orla A O'Mahony
1Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-0618, USA. drobins@umich.edu
Abstract:
Androgen, acting via the androgen receptor (AR), is central to male development, differentiation and hormone-dependent diseases such as prostate cancer. AR is actively involved in the initiation of prostate cancer, the transition to androgen independence, and many mechanisms of resistance to therapy. To examine genetic variation of AR in cancer, we created mice by germ-line gene targeting in which human AR sequence replaces that of the mouse. Since shorter length of a polymorphic N-terminal glutamine (Q) tract has been linked to prostate cancer risk, we introduced alleles with 12, 21 or 48 Qs to test this association. The three "humanized" AR mouse strains (h/mAR) are normal physiologically, as well as by cellular and molecular criteria, although slight differences are detected in AR target gene expression, correlating inversely with Q tract length. However, distinct allele-dependent differences in tumorigenesis are evident when these mice are crossed to a transgenic prostate cancer model. Remarkably, Q tract variation also differentially impacts disease progression following androgen depletion. This finding emphasizes the importance of AR function in androgen-independent as well as androgen-dependent disease. These mice provide a novel genetic paradigm in which to dissect opposing functions of AR in tumor suppression versus oncogenesis.
Insights
Androgen receptor (AR) gene variation impacts prostate cancer development and progression. Shorter AR glutamine tracts influence tumor growth and resistance to therapy, highlighting AR
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- Androgen receptor (AR) is crucial for male development and prostate cancer.
- AR plays a role in prostate cancer initiation, progression to androgen independence, and therapy resistance.
- Genetic variation in AR, particularly the N-terminal glutamine (Q) tract length, is linked to prostate cancer risk.
Purpose of the Study:
- To investigate the impact of AR genetic variation on prostate cancer.
- To create and characterize humanized AR (h/mAR) mouse models with varying Q tract lengths.
- To analyze the role of AR Q tract length in both androgen-dependent and androgen-independent prostate cancer.
Main Methods:
- Germ-line gene targeting to replace mouse AR with human AR sequence.
- Generation of three h/mAR mouse strains with 12, 21, or 48 Q residues in the AR N-terminal tract.
- Crossing h/mAR mice with a transgenic prostate cancer model to study tumorigenesis and disease progression.
- Assessment of physiological normality, AR target gene expression, and tumor development.
Main Results:
- h/mAR mice with varying Q tract lengths are physiologically normal but show slight differences in AR target gene expression inversely correlated with Q tract length.
- Distinct allele-dependent differences in prostate tumorigenesis were observed when h/mAR mice were crossed with a prostate cancer model.
- AR Q tract variation differentially affected disease progression, including during androgen depletion, indicating roles in both androgen-dependent and independent disease.
Conclusions:
- AR Q tract length is a significant genetic factor influencing prostate cancer initiation and progression.
- Humanized AR mouse models with defined Q tract lengths are valuable tools for studying AR function in cancer.
- Understanding AR variation is critical for developing effective therapies for all stages of prostate cancer, including castration-resistant disease.
