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Mutant androgen receptors in prostatic tumors distinguish between amino‐acid‐sequence requirements for transactivation and ligand binding
Author(s) -
Peterziel Heike,
Culig Zoran,
Stober Jutta,
Hobisch Alfred,
Radmayr Christian,
Bartsch Georg,
Klocker Helmut,
Cato Andrew C. B.
Publication year - 1995
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910630415
Subject(s) - transactivation , androgen receptor , receptor , mutant , androgen , prostate cancer , biology , androgen receptor antagonists , nuclear receptor , endocrinology , chemistry , cancer research , biochemistry , medicine , hormone , cancer , genetics , transcription factor , gene
Abstract Mutant androgen receptors are thought to contribute to hormone resistance in prostate carcinoma. The part they play in this process, however, is ill‐defined. Here we report on transactivation by 2 mutant androgen receptors from prostatic tumors with single amino‐acid exchanges in their hormone‐binding domains. These exchanges enhance the transactivation property of the receptors, particularly to androsterone and androstanediol, 2 metabolized derivatives of testosterone present in the prostate. Additionally, they enhance the transactivation potential of the mutant receptors to hydroxyflutamide, an anti‐androgen frequently used in hormone ablation therapy. The increased transactivation by the mutant receptors did not result from altered affinity of the receptors to the inducing ligands nor from measurable changes in conformation of the liganded receptors. Thus the single amino‐acid exchanges identify differences in amino‐acid‐sequence requirements for transactivation and ligand binding in the hormone‐binding domain of the androgen receptor. These results provide new insights into ligand‐dependent transactivation, and form a framework for the search for effective antagonists to be used in prostate‐cancer therapy.