Androgen mediated regulation and functional implications of fkbp51 expression in prostate cancer.
OBJECTIVE
Androgen ablation continues to be the most effective therapy for metastatic prostate cancer, although the biologically active androgen receptor (AR) target genes remain largely unknown. Because AR signaling continues in hormone refractory disease, effector AR target genes may have therapeutic import.


METHODS
We used oligonucleotide microarrays to identify genes with expression induced by androgen and associated with androgen independent growth. The androgen induced expression of FKBP51, a steroid receptor chaperone, was further investigated in LNCaP cells by Northern and Western analysis, and in primary prostate specimens using immunohistochemistry. We used stable clones over expressing FKBP51 to test the functional effects of FKBP51.


RESULTS
Many genes had expression that correlates with androgen stimulation in LNCaP cells but relatively few had reproducible, androgen mediated changes in expression across multiple prostate cancer cell lines. FKBP51 had androgen induced RNA and protein expression in LNCaP cells and decreased expression in normal prostate epithelial cells following castration. Further study demonstrated that FKBP51 induction was not a generalized response to cell proliferation, FKBP51 protein physically interacts with AR and LNCaP cells constitutively over expressing FKBP51 have increased ligand mediated AR activation of an exogenous AR reporter construct and endogenous prostate specific antigen.


CONCLUSIONS
Taken together these results confirm FKBP51 as an androgen induced gene, demonstrate a physical interaction between FKBP51 and AR and suggest that FKBP51 over expression increases AR transcriptional activity in prostate cancer.
Febbo
Phillip G
PG
Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Lowenberg
Mark
M
Thorner
Aaron R
AR
Brown
Myles
M
Loda
Massimo
M
Golub
Todd R
TR
D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000502:physiology*; D022021:Tacrolimus Binding Proteins / Q000096:biosynthesis*; D000099159:Tacrolimus Binding Protein 5
D018841:HSP90 Heat-Shock Proteins; D011944:Receptors, Androgen; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5