Article

Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason score and chromosome 8p deletion.

Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Baltimore, MD, USA.
Cancer Research (impact factor: 7.86). 12/2006; 66(22):10683-90. DOI:10.1158/0008-5472.CAN-06-0963 pp.10683-90
Source: PubMed

ABSTRACT NKX3.1 is a homeobox gene located at chromosome 8p21.2, and one copy is frequently deleted in prostate carcinoma. Prior studies of NKX3.1 mRNA and protein in human prostate cancer and prostatic intraepithelial neoplasia (PIN) have been conflicting, and expression in focal prostate atrophy lesions has not been investigated. Immunohistochemical staining for NKX3.1 on human tissue microarrays was decreased in most focal atrophy and PIN lesions. In carcinoma, staining was inversely correlated with Gleason grade. Fluorescence in situ hybridization showed that no cases of atrophy had loss or gain of 8p, 8 centromere, or 8q24 (C-MYC) and only 12% of high-grade PIN lesions harbored loss of 8p. By contrast, NKX3.1 staining in carcinoma was correlated with 8p loss and allelic loss was inversely related to Gleason pattern. Quantitative reverse transcription-PCR for NKX3.1 mRNA using microdissected atrophy revealed a concordance with protein in five of seven cases. In carcinoma, mRNA levels were decreased in 6 of 12 cases but mRNA levels correlated with protein levels in only 4 of 12 cases, indicating translational or post-translational control. In summary, NKX3.1 protein is reduced in focal atrophy and PIN but is not related to 8p allelic loss in these lesions. Therefore, whereas genetic disruption of NKX3.1 in mice leads to PIN, nongenetic mechanisms reduce NKX3.1 protein levels early in human prostate carcinogenesis, which may facilitate both proliferation and DNA damage in atrophic and PIN cells. Monoallelic deletions on chromosome 8p are associated with more advanced invasive and aggressive disease.

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Keywords

8 centromere
 
8p allelic loss
 
aggressive disease
 
DNA damage
 
focal atrophy
 
focal prostate atrophy lesions
 
genetic disruption
 
Gleason grade
 
Gleason pattern
 
high-grade PIN lesions harbored loss
 
microdissected atrophy
 
mRNA levels
 
mRNA levels correlated
 
NKX3.1 protein
 
NKX3.1 protein levels
 
PIN cells
 
PIN lesions
 
prostate carcinoma
 
protein levels
 
situ hybridization
 

Carlise R Bethel