Neutral endopeptidase protein expression and prognosis in localized prostate cancer.
OBJECTIVE
Neutral endopeptidase (NEP) is a cell-surface peptidase that inactivates neuropeptide growth factors implicated in prostate cancer progression. The clinical significance of decreased NEP expression observed in prostate cancer is unclear. We investigated whether decreased NEP expression in localized prostate cancers is associated with prostate-specific antigen (PSA) relapse after radical prostatectomy.


METHODS
NEP expression patterns were examined by immunohistochemistry in 223 men, who underwent radical prostatectomy between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) with available representative tissues and adequate follow up. We also examined whether hypermethylation of the NEP promoter contributes to down-regulation of NEP protein expression in a subset of patients that showed decreased NEP expression (n = 22).


RESULTS
Three patterns of NEP expression were observed: (a) membranous expression similar to benign prostate epithelium (n = 82; 37%); (b) complete loss of NEP expression in prostate cancer compared with adjacent benign prostate glands (n = 105; 47%); and (c) heterogeneous NEP expression (n = 36; 16%). In a multivariate analysis, complete loss of NEP expression was associated with PSA relapse after controlling for grade, stage, pretreatment PSA, and race simultaneously (hazard ratio, 1.99; 95% confidence interval, 1.13-3.52; two-sided chi(2) P = 0.017). In addition, DNA hypermethylation of the NEP promoter was frequently (73%) identified in a subset of 22 of cases that showed decreased NEP expression.


CONCLUSIONS
Our data suggest that decreased NEP expression might contribute to progression of localized prostate cancer after surgery. Data also suggest that methylation is an important mechanism of NEP protein silencing. Larger prospective studies are required for confirmation.
Osman
Iman
I
Department of Urology, New York University Cancer Institute, Kaplan Comprehensive Cancer Center, New York, New York, USA. Iman.Osman@med.nyu.edu
Yee
Herman
H
Taneja
Samir S
SS
Levinson
Benjamin
B
Zeleniuch-Jacquotte
Anne
A
Chang
Caroline
C
Nobert
Craig
C
Nanus
David M
DM
D019175:DNA Methylation; D018450:Disease Progression; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D015999:Multivariate Analysis; D015260:Neprilysin / Q000096:biosynthesis* / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000201:enzymology* / Q000473:pathology
D017430:Prostate-Specific Antigen; D015260:Neprilysin