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Functional analysis of 44 mutant androgen receptors from human prostate cancer
Xu-Bao Shi1, Ai-Hong Ma, Liang Xia
1Department of Urology, University of California, Davis, School of Medicine, Sacramento, California 95817, USA.
Abstract:
Mutations of the androgen receptor gene are believed to contribute to the androgen-independent growth of prostate cancer cells. To date, 56 missense mutations of the androgen receptor have been identified in human prostate cancer. The functional status of most of these mutants has not yet been investigated. To address their functional properties, we generated 44 androgen receptor mutants that have been identified in human prostate cancer and used a colorimetric yeast reporter assay to analyze their transactivational activities in response to seven different ligands. We found that these mutant androgen receptors exhibited diverse transactivational activity: seven (16%) showed loss of function, three (7%) had wild-type function, 14 (32%) had partial function, and 20 (45%) had gains of function. Five of 20 gain-of-function mutants had promiscuous activity, being transactivated by non-androgens. We also found that the combination of estradiol and progesterone at physiological concentrations weakly or moderately activated an additional seven mutant androgen receptors. Our findings provide essential information for understanding the role of mutant androgen receptors in prostate cancer.
Insights
Androgen receptor (AR) mutations drive prostate cancer growth. This study analyzed 44 AR mutants, finding diverse functions including gain-of-function and promiscuous activity, crucial for understanding cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Androgen receptor (AR) gene mutations are implicated in androgen-independent prostate cancer growth.
- Numerous AR missense mutations (56 identified) exist in human prostate cancer, but their functions are largely uncharacterized.
Purpose of the Study:
- To functionally characterize 44 identified androgen receptor mutants in human prostate cancer.
- To investigate the transactivational activities of these mutants in response to various ligands.
Main Methods:
- Generated 44 androgen receptor mutants identified in human prostate cancer.
- Utilized a colorimetric yeast reporter assay to assess transactivational activity.
- Tested mutant responses to seven different ligands.
Main Results:
- Mutant ARs displayed varied activities: 16% loss-of-function, 7% wild-type, 32% partial function, and 45% gain-of-function.
- Five gain-of-function mutants showed promiscuous activity, activated by non-androgens.
- Estradiol and progesterone activated seven additional mutant ARs at physiological concentrations.
Conclusions:
- Mutant androgen receptors exhibit diverse functional properties, including altered ligand binding and activation.
- Understanding these mutant AR functions is essential for elucidating their role in prostate cancer progression.
- Findings highlight potential therapeutic targets by revealing non-androgen-mediated activation pathways.