Forkhead protein FKHR and its phosphorylated form p-FKHR in human prostate cancer.
In vitro studies suggest that the proapoptotic function of forkhead protein FKHR is probably inactivated by means of phosphorylation through the protein kinase B pathway. However, the clinical significance of FKHR in prostate cancer remains unclear. Six hundred forty radical prostatectomies were used for building tissue microarrays. Slides were stained with antibodies against FKHR and phosphorylated FKHR (p-FKHR). Correlations with clinicopathologic parameters were analyzed by Spearman rank test. Cox regression test and Kaplan-Meier test were used to determine the probability of disease recurrence, which is defined as a serum prostate-specific antigen (PSA) level greater than 0.4 ng/mL after radical prostatectomy. Nuclear FKHR level was higher in normal prostate than in benign prostatic hyperplasia and prostate cancer (P = .0000). Nuclear expression of FKHR was correlated with preoperative PSA level (rho = 0.108, P = .029), extracapsular extension (rho = 0.137, P = .005), and seminal vesicle invasion (rho = 0.101, P = .039). FKHR expression was not a significant indicator of biochemical failure by either univariate or multivariate analysis. Nuclear p-FKHR expression correlated with patients' age (rho = 0.179, P = .0003), Gleason score (rho = 0.130, P = .0083), extracapsular extension (rho = 0.227, P = .0000), clinical stage (Union Internationale Contre le Cancer system) (rho = 0.166, P = .0007), and lymph node status (rho = 0.101, P = .0401). Cytoplasmic p-FKHR correlated with patients' age (rho = 0.146, P = .0030) and clinical stage (rho = 0.117, P = .0180). Cytoplasmic p-FKHR was a significant indicator of biochemical recurrence (P = .0164; hazard ratio, 1.114-2.929). Nuclear p-FKHR strongly correlated with phosphorylated protein kinase B (rho = 0.368, P = .0000), androgen receptor (rho = 0.385, P = .0000), and Skp-2 (rho = 0.170, P = .0036). Our data suggest that the proapoptotic role of FKHR is probably regulated by several signaling pathways in prostate cancer.
Li
Rile
R
Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
Erdamar
Sibel
S
Dai
Hong
H
Wheeler
Thomas M
TM
Frolov
Anna
A
Scardino
Peter T
PT
Thompson
Timothy C
TC
Ayala
Gustavo E
GE
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology; D014408:Biomarkers, Tumor / Q000032:analysis*; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D011944:Receptors, Androgen; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017430:Prostate-Specific Antigen