Distinct Altered Patterns of p27KIP1 Gene Expression in Benign Prostatic Hyperplasia and Prostatic Carcinoma

Abstract

Background: The p27^KIP1 gene, whose protein product is a negative regulator of the cell cycle, is a potential tumor suppressor gene; however, no tumor-specific mutations of this gene have been found in humans. This study was undertaken to identify and to assess potential alterations of p27^KIP1 gene expression in patients with benign prostatic hyperplasia (BPH) and patients with prostate cancer. Methods: We analyzed 130 prostate carcinomas from primary and metastatic sites, as well as prostate samples from normal subjects and from patients with BPH. Immunohistochemistry and in situ hybridization were used to determine the levels of expression and the microanatomical localization of p27 protein and messenger RNA (mRNA), respectively. Immunoblotting and immunodepletion assays were performed on a subset of the prostate tumors. Associations between alterations in p27^KIP1 expression and clinicopathologic variables were evaluated with a nonparametric test. The Kaplan-Meier method and the logrank test were used to compare disease-relapse-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 p27^KIP1 mRNA in both epithelial cells and stromal cells. However, p27 protein and p27^KIP1 mRNA were almost undetectable in epithelial cells 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 prostate carcinomas expressing lower levels of p27 protein appeared to be biologically more aggressive (two-sided P = .019 [Cox regression analysis]). Conclusions/Implications: On the basis of these results, we infer that loss of p27^KIP1 expression in the human prostate may be causally linked to BPH and that BPH is not a precursor to prostate cancer. [J Natl Cancer Inst 1998;90:1284- 91]