The androgen receptor (AR) acting as a transcription factor plays a pivotal role in the occurrence and progression of prostate cancer (CaP). Several AR-related factors or modulators have been reported to influence AR activity. Whether and how these factors cooperatively modulate the AR activity has not been well defined. In the present study, the combined effect of p160 coactivators, short CAG length (encoding a short polyQ tract), and AR mutations on AR transactivation in a yeast system was evaluated. It was found that the short polyQ tract can upregulate the transactivation of the wild-type (WT) AR and partial-function (PF) AR mutants in response to a physiological level (10−9 M) of dihydrotestosterone. Addition of a p160 coactivator (SRC-1 or TIF2) to the above systems resulted in a significant increase in the ligand-stimulated transactivation. Although the androgen antagonist bicalutamide could suppress the activity of androgen-activated WT or PF ARs, it was unable to do so for gain-of-function AR mutants. A combination of the short polyQ tract and coactivator TIF2 acted cooperatively on the WT AR and PF AR mutants to enhance their transactivation in response to either a low level of dihydrotestosterone (10−10 M) or adrenal dehydroepiandrosterone. Taken together, this finding suggests that the modulated AR activity may involve early in the carcinogenesis of CaP. Additionally, these data support the concept that a given CaP in which the AR activity is modulated by multiple AR modulators may progress more readily to castrate resistance.
EllemSJ, RisbridgerGP. Treating prostate cancer: A rationale for targeting local oestrogens. Nat Rev Cancer, 2007; 7:621.
3.
ChangSS, KibelAS. The role of systemic cytotoxic therapy for prostate cancer. BJU Int, 2009; 103:8.
4.
PetrioliR, FiaschiAI, FranciniEet al.The role of doxorubicin and epirubicin in the treatment of patients with metastatic hormone-refractory prostate cancer. Cancer Treat Rev, 2008; 34:710.
5.
DebesJD, TindallDJ. Mechanisms of androgen-refractory prostate cancer. N Engl J Med, 2004; 351:1488.
6.
ChenCD, WelsbieDS, TranCet al.Molecular determinants of resistance to antiandrogen therapy. Nat Med, 2004; 10:33.
7.
GregoryCW, HeB, JohnsonRTet al.A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res, 2001; 61:4315.
8.
LouieMC, YangHQ, MaAHet al.Androgen-induced recruitment of RNA polymerase II to a nuclear receptor-p160 coactivator complex. Proc Natl Acad Sci U S A, 2003; 100:2226.
9.
BevanCL, HoareS, ClaessensFet al.The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1. Mol Cell Biol, 1999; 19:8383.
10.
BuchananG, YangM, CheongAet al.Structural and functional consequences of glutamine tract variation in the androgen receptor. Hum Mol Genet, 2004; 13:1677.
11.
GiovannucciE, StampferMJ, KrithivasKet al.The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci U S A, 1997; 94:3320.
12.
StanfordJL, JustJJ, GibbsMet al.Polymorphic repeats in the androgen receptor gene: Molecular markers of prostate cancer risk. Cancer Res, 1997; 57:1194.
13.
FentonMA, ShusterTD, FertigAMet al.Functional characterization of mutant androgen receptors from androgen-independent prostate cancer. Clin Cancer Res, 1997; 3:1383.
14.
ShiXB, MaAH, XiaLet al.Functional analysis of 44 mutant androgen receptors from human prostate cancer. Cancer Res, 2002; 62:1496.
15.
SouthwellJ, ChowdhurySF, GottliebBet al.An investigation into CAG repeat length variation and N/C terminal interactions in the T877A mutant androgen receptor found in prostate cancer. J Steroid Biochem Mol Biol, 2008; 111:138.
16.
McEwanIJ. Investigation of steroid receptor function in the budding yeast Saccharomyces cerevisiae. FEMS Microbiol Lett, 1999; 176:1.
17.
PurvisIJ, ChotaiD, DykesCWet al.An androgen-inducible expression system for Saccharomyces cerevisiae. Gene, 1991; 106:35.
NazarethLV, StenoienDL, BingmanWE 3rd. et al.A C619Y mutation in the human androgen receptor causes inactivation and mislocalization of the receptor with concomitant sequestration of SRC-1 (steroid receptor coactivator 1)Mol Endocrinol, 1999; 13:2065.
20.
MeyerT, StarrDB, Carlstedt-DukeJ. The rat glucocorticoid receptor mutant K461A differentiates between two different mechanisms of transrepression. J Biol Chem, 1997; 272:21090.
21.
AarnisaloP, SanttiH, PoukkaHet al.Transcription activating and repressing functions of the androgen receptor are differentially influenced by mutations in the deoxyribonucleic acid-binding domain. Endocrinology, 1999; 140:3097.
22.
UhtRM, WebbP, NguyenPet al.A conserved lysine in the estrogen receptor DNA binding domain regulates ligand activation profiles at AP-1 sites, possibly by controlling interactions with a modulating repressor. Nucl Recept, 2004; 2:2.
23.
HsingAW, GaoYT, WuGet al.Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: A population-based case-control study in China. Cancer Res, 2000; 60:5111.
24.
IrvineRA, YuMC, RossRKet al.The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res, 1995; 55:1937.
25.
ChoongCS, KemppainenJA, ZhouZXet al.Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol Endocrinol, 1996; 10:1527.
26.
ChamberlainNL, DriverED, MiesfeldRL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res, 1994; 22:3181.
27.
CudeKJ, MontgomeryJS, PriceDKet al.The role of an androgen receptor polymorphism in the clinical outcome of patients with metastatic prostate cancer. Urol Int, 2002; 68:16.
28.
AgoulnikIU, VaidA, NakkaMet al.Androgens modulate expression of transcription intermediary factor 2, an androgen receptor coactivator whose expression level correlates with early biochemical recurrence in prostate cancer. Cancer Res, 2006; 66:10594.
29.
AgoulnikIU, VaidA, BingmanWE3rd. et al.Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression. Cancer Res, 2005; 65:7959.
30.
KangZ, JanneOA, PalvimoJJ. Coregulator recruitment and histone modifications in transcriptional regulation by the androgen receptor. Mol Endocrinol, 2004; 18:2633.
31.
MiyamotoH, YehS, WildingGet al.Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells. Proc Natl Acad Sci U S A, 1998; 95:7379.
32.
ComuzziB, LambrinidisL, RogatschHet al.The transcriptional co-activator cAMP response element-binding protein-binding protein is expressed in prostate cancer and enhances androgen- and anti-androgen-induced androgen receptor function. Am J Pathol, 2003; 162:233.
33.
HobischA, HoffmannJ, LambrinidisLet al.Antagonist/agonist balance of the nonsteroidal antiandrogen bicalutamide (Casodex) in a new prostate cancer model. Urol Int, 2000; 65:73.
34.
MasielloD, ChengS, BubleyGJet al.Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor. J Biol Chem, 2002; 277:26321.
35.
HaraT, MiyazakiJ, ArakiHet al.Novel mutations of androgen receptor: A possible mechanism of bicalutamide withdrawal syndrome. Cancer Res, 2003; 63:149.
36.
CuligZ, HoffmannJ, ErdelMet al.Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system. Br J Cancer, 1999; 81:242.
37.
HeB, BowenNT, MingesJTet al.Androgen-induced NH2- and COOH-terminal Interaction Inhibits p160 coactivator recruitment by activation function 2. J Biol Chem, 2001; 276:42293.
38.
BonaguraTW, DengM, BrownTR. A naturally occurring mutation in the human androgen receptor of a subject with complete androgen insensitivity confers binding and transactivation by estradiol. Mol Cell Endocrinol, 2007; 263:79.
39.
HsiaoPW, LinDL, NakaoRet al.The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. J Biol Chem, 1999; 274:20229.
40.
MhatreAN, TrifiroMA, KaufmanMet al.Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy. Nat Genet, 1993; 5:184.
41.
LabrieF, DupontA, GiguereMet al.Benefits of combination therapy with flutamide in patients relapsing after castration. Br J Urol, 1988; 61:341.
42.
TanJ, ShariefY, HamilKGet al.Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol, 1997; 11:450.
43.
RijkJC, BoveeTF, GrootMJet al.Evidence of the indirect hormonal activity of prohormones using liver S9 metabolic bioactivation and an androgen bioassay. Anal Bioanal Chem, 2008; 392:417.
44.
MiyamotoH, YehS, LardyHet al.Delta5-androstenediol is a natural hormone with androgenic activity in human prostate cancer cells. Proc Natl Acad Sci U S A, 1998; 95:11083.
MoQ, LuSF, HuSet al.DHEA and DHEA sulfate differentially regulate neural androgen receptor and its transcriptional activity. Brain Res Mol Brain Res, 2004; 126:165.
47.
MarcelliM, IttmannM, MarianiSet al.Androgen receptor mutations in prostate cancer. Cancer Res, 2000; 60:944.
48.
TilleyWD, BuchananG, HickeyTEet al.Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin Cancer Res, 1996; 2:277.
49.
CeralineJ, ErdmannE, ErbsPet al.A yeast-based functional assay for the detection of the mutant androgen receptor in prostate cancer. Eur J Endocrinol, 2003; 148:99.
50.
KashiwagiB, ShibataY, OnoYet al.Changes in testosterone and dihydrotestosterone levels in male rat accessory sex organs, serum, and seminal fluid after castration: Establishment of a new highly sensitive simultaneous androgen measurement method. J Androl, 2005; 26:586.
