DISTINCT ALTERED PATTERNS OF P27(KIP1) GENE-EXPRESSION IN BENIGN PROSTATIC HYPERPLASIA AND PROSTATIC-CARCINOMA

Background: The p27(KIP1) gene, whose protein product is a negative re gulator of the cell cycle, is a potential tumor suppressor gene; howev er, no tumor-specific mutations of this gene have been found in humans , This study was undertaken to identify and to assess potential altera tions of p27(KIP1) gene expression in patients with benign prostatic h yperplasia (BPH) and patients with prostate cancer, Methods: We analyz ed 130 prostate carcinomas from primary and metastatic sites, as well as prostate samples from normal subjects and from patients with BPH. I mmunohistochemistry and in situ hybridization were used to determine t he levels of expression and the microanatomical localization of p27 pr otein and messenger RNA (mRNA), respectively. Immunoblotting and immun odepletion assays mere performed on a subset of the prostate tumors. a ssociations between alterations in p27(KIP1) expression and clinicopat hologic variables were evaluated with a nonparametric test. The Kaplan -Meier method and the logrank test were used to compare disease-relaps e-free survival. Prostate tissues of p27(KIP1) null (i.e., knock-out) and wild-type mice were also evaluated, Results: Normal human prostate tissue exhibited abundant amounts of p27 protein and high levels of p 27(KIP1) mRNA in both epithelial cells and stromal cells. However, p27 protein and p27(KIP1) mRNA were almost undetectable in epithelial cel ls and stromal cells of BPH lesions, Furthermore, p27(KIP1) null mice developed enlarged (hyperplastic) prostate glands. In contrast to BPH, prostate carcinomas were found to contain abundant p27(KIP1) mRNA but either high or low to undetectable levels of p27 protein, Primary pro state carcinomas expressing lower levels of p27 protein appeared to be biologically more aggressive (two-sided P = .019 [Cox regression anal ysis]). Conclusions/Implications: On the basis of these results, we in fer that loss of p27(KIP1) expression in the human prostate may be cau sally linked to BPH and that BPH is not a precursor to prostate cancer .