Molecular characterization of the p53 and RB1 tumor suppressor pathways in human prostate carcinomas

The p53 and RB1 tumor suppressor genes play critical roles in the negative regulation of the cell cycle, response to DNA damage, and apoptosis. One or both of these genes are often found mutated or deleted in many types of human cancer. As the molecular circuitry of these suppressor pathways is emerging, we sought to characterize abnormalities found in both pathways in human prostate carcinoma (CaP) by focusing on the tumor suppressor and its associated cyclin-dependent kinase (CDK) inhibitor in each. CDKN1 encodes a CDK inhibitor downstream in the p53 pathway and when induced by wild-type p53, results in cell cycle arrest. CDKN2 encodes a CDK inhibitor, upstream in the RB1 pathway, involved in the regulation of RB1 phosphorylation: loss of CDKN2 activity yields hyperphosphorylated RB1 and continued cell cycling. RT-PCR, SSCP analysis, and DNA sequencing were used to assess the expression of all four genes. Altered p53 expression was found in 34/102 (33%) CaPs, and 35/83 (43%) showed low CDKN1 expression. 24/51 (47%) showed abnormalities in one of these genes in the p53 pathway. Altered expression of RB1 and CDKN2 was observed in 17/102 (17%) and 39/82 (48%), respectively. 31/51 (61%) showed abnormalities in one of these genes in the RB1 pathway. Overall, of 51 CaPs, 38 (75%) showed abnormalities in at least one of the four genes and 17 (33%) showed abnormalities of a gene in both pathways. The understanding of the molecular abnormalities in individual tumors, related to cell cycle biology and patient characteristics, may lead to improved therapy for CaP patients.