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.
Highlights
Prostatic adenocarcinoma is one of the most common malignancies, representing the second leading cause of cancer death in American men [1]
That loss of one allele of NKX3.1 occurs early in prostate carcinogenesis is evidenced by the finding that loss of heterozygosity (LOH) on chromosome 8p has been reported to occur in high-grade prostatic intraepithelial neoplasia (PIN), a lesion that is a putative precursor to many invasive prostatic carcinomas [6], at a frequency between 20% and 80% [7,8,9]
We report the results of the following: (a) a quantitative analysis of the expression of NKX3.1 protein using a novel anti-NKX3.1 polyclonal antibody on tissue microarrays (TMA) containing matched samples of normal, focal prostate atrophy, PIN, and clinically localized adenocarcinoma of various Gleason grades; (b) a study to correlate NKX3.1 protein levels with chromosomal alterations on chromosome 8 using fluorescence in situ hybridization (FISH) on the same TMA specimens; and (c) a study to determine if NKX3.1 protein levels correlate with mRNA levels using laser capture microdissection of frozen tissue specimens for quantitative reverse transcription-PCR (RT-PCR)
Summary
Prostatic adenocarcinoma is one of the most common malignancies, representing the second leading cause of cancer death in American men [1]. NKX3.1 is located on chromosome 8p21.2 within a region that shows loss of heterozygosity (LOH) in prostate cancer. That loss of one allele of NKX3.1 occurs early in prostate carcinogenesis is evidenced by the finding that LOH on chromosome 8p has been reported to occur in high-grade prostatic intraepithelial neoplasia (PIN), a lesion that is a putative precursor to many invasive prostatic carcinomas [6], at a frequency between 20% and 80% [7,8,9]. Nkx3.1 homozygous mutant mice do not develop invasive carcinoma, epithelial hyperplasia and PIN lesions arise with age. These compound mutants develop PIN lesions that progress to invasive carcinomas and at times to metastatic disease. Because the effects are seen in NKX3.1 heterozygotes, haploinsufficiency of Nkx3.1 seems to play a role in tumor progression
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