Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation.
Cyclin D1 is a multifaceted regulator of both transcription and cell-cycle progression that exists in two distinct isoforms, cyclin D1a and D1b. In the prostate, cyclin D1a acts through discrete mechanisms to negatively regulate androgen receptor (AR) activity and thus limit androgen-dependent proliferation. Accordingly, cyclin D1a is rarely overexpressed in prostatic adenocarcinoma and holds little prognostic value in this tumor type. However, a common polymorphism (A870) known to facilitate production of cyclin D1b is associated with increased prostate cancer risk. Here we show that cyclin D1b is expressed at high frequency in prostate cancer and is up-regulated in neoplastic disease. Furthermore, our data demonstrate that, although cyclin D1b retains AR association, it is selectively compromised for AR regulation. The altered ability of cyclin D1b to regulate the AR was observed by using both in vitro and in vivo assays and was associated with compromised regulation of AR-dependent proliferation. Consistent with previous reports, expression of cyclin D1a inhibited cell-cycle progression in AR-dependent prostate cancer cells. Strikingly, cyclin D1b significantly stimulated proliferation in this cell type. AR-negative prostate cancer cells were nonresponsive to cyclin D1 (a or b) expression, indicating that defects in AR corepressor function yield a growth advantage specifically in AR-dependent cells. In summary, these studies indicate that the altered AR regulatory capacity of cyclin D1b contributes to its association with increased prostate cancer risk and provide evidence of cyclin D1b-mediated transcriptional regulation.
Burd
Craig J
CJ
Department of Cell Biology, University of Cincinnati, Cincinnati, OH 45267, USA.
Petre
Christin E
CE
Morey
Lisa M
LM
Wang
Ying
Y
Revelo
Monica P
MP
Haiman
Christopher A
CA
Lu
Shan
S
Fenoglio-Preiser
Cecilia M
CM
Li
Jiwen
J
Knudsen
Erik S
ES
Wong
Jiemin
J
Knudsen
Karen E
KE
D000728:Androgens / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D000728:Androgens; D020033:Protein Isoforms; D011944:Receptors, Androgen; D012097:Repressor Proteins; D019938:Cyclin D1; D017430:Prostate-Specific Antigen