LOSS OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P27(KIP1) PROTEIN IN HUMAN PROSTATE-CANCER CORRELATES WITH TUMOR GRADE

Loss of expression or mutational deletion of the cyclin-dependent kina se inhibitor p27(Kip1) has recently been implicated in malignant devel opment. In this study, we investigated the relationship between p27(Ki p1) protein expression and tumor grade in human prostate cancer by con ducting an immunohistochemical analysis in a series of normal prostate , benign prostatic hyperplasia, and malignant prostate cancer specimen s. The proliferative activity of prostatic tumors was determined on th e basis of the Ki-67 nuclear antigen staining. A uniformly intense imm unoreactivity for p27(Kip1) was localized to the nuclei of glandular e pithelial cells of normal prostates. The benign glandular epithelia ex hibited moderate immunostaining. In the malignant prostate tissue, how ever, a heterogeneous pattern of substantially reduced p27(Kip1) immun oreactivity was found among the glandular epithelial cells. The majori ty of primary prostate cancer specimens (68%) were totally negative fo r p27(Kip1) immunoreactivity, whereas the rest exhibited a significant ly decreased p27(Kip1) expression, compared with the normal prostate ( P < 0.01). Moreover, there was progressively diminished p27(Kip1) immu nostaining with increased tumor grade. This loss of p27(Kip1) was asso ciated with an increase in the proliferative index of prostatic tumors (r = 0.88). There was no significant relationship between p27(Kip) lo ss and the transforming growth factor beta receptor status of prostati c adenocarcinomas. These results indicate that frequent loss of the cy clin-dependent kinase inhibitor p27(Kip1) in human prostate cancer cel ls correlates with advancing histological aggressiveness, implicating deregulation of p27(Kip1) in prostate tumor progression.