Androgen receptor mutants detected in recurrent prostate cancer exhibit diverse functional characteristics.
BACKGROUND
Alterations in the function of androgen receptor (AR) and its signaling pathway may be responsible for the progression of prostate cancer. The goal of the present study was to investigate the potential roles of AR structural and functional alterations in the progression of prostate cancer, and the relationship between the structure and function of the AR.


METHODS
AR gene in 58 prostate cancer samples was examined for mutations using PCR-single strand conformation polymorphism (SSCP) analysis and DNA sequencing. Effects of mutations on the structure and function of AR were investigated by androgen-binding assays and transactivation assays, respectively.


RESULTS
Four novel somatic mutations (G142V, D221H, E872Q, and M886I) were identified from recurrent prostate cancer samples. None of the AR mutants differed from wild-type AR (wtAR) in their abilities to bind the synthetic androgen methyltrienolone. However, these mutated AR exhibited diverse functional characteristics as compared with wtAR. G142V and D221H showed increased responses to DHT. E872Q could be abnormally activated by 17beta-estradiol, progesterone, and cyproterone acetate (CPA). Furthermore, E872Q and M886I presented increased responses to DHT in the presence of coactivators TIF-2 and CBP, but not p300. On the other hand, although overexpression of corepressors N-CoR and SMRT could result in evident inhibition on DHT- or CPA-induced transactivity of wtAR and the AR mutants, N-CoR displayed stronger inhibitory effects on DHT-induced transactivity of the AR mutants (especially for E872Q and M886I) than that of wtAR. To our knowledge, this is the first characterization of enhanced inhibitory effects of corepressors on the transactivity of the AR mutants found in prostate cancer.


CONCLUSIONS
The data presented here demonstrate that AR mutants found in prostate cancer had different functional alterations, which might play an important role in the progression of prostate cancer.
Chen
Guangchun
G
Department of Pathophysiology, Second Military Medical University, Shanghai, People's Republic of China.
Wang
Xiaohui
X
Zhang
Shimin
S
Lu
Ying
Y
Sun
Yinghao
Y
Zhang
Jinshan
J
Li
Zongbin
Z
Lu
Jian
J
D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000728:Androgens; D011944:Receptors, Androgen