Defects of DNA mismatch repair in human prostate cancer

Loss of mismatch repair (MMR) function leads to the accumulation of errors that normally occur during DNA replication, resulting in genetic instabilit y. Germ-line mutations of MMR genes in the patients with hereditary nonpoly posis colorectal cancer lead to inactivation of MMR protein functions, and the defects of MMR are well correlated to the high rate of microsatellite i nstability in their tumors. Previous studies (T. Uchida, et al. Oncogene, 1 0: 1019-1022, 1995; S. Egawa, et al. Cancer Res., 55: 2418-2421., 1995; J. M. Cunningham, st al. Cancer Res., 56: 4475-4482, 1996; X. Gao, et al. Onco gene, 9: 2999-3003, 1994; H. Rohrbach, et al. Prostate, 40: 20-27, 1999) ha ve shown that genetic instability (chromosomal and microsatellite instabili ty) is detectable in human prostate cancer. To elucidate the role of MMR ge nes in the tumorigenesis of prostate cancer, we evaluated the expression of these genes in human cancer cell lines and in tumor specimens. Using Weste rn blot analysis, we detected toss among MSH2, MLH1, PMS2, and PMS1 protein s in DU145, LNCaP, p69SV40T, M2182, and M12 cells. In addition, genomic ins tability in the prostate cell lines including DU145, PC3, LNCaP, p67SV40T, M2182, and R M12 was detected by a microsatellite mutation assay. Significa ntly, immunohistochemical analysis of prostatic tissue revealed the reducti on or absence of MMR protein expression in the epithelium of prostate tumor foci compared with normal adjacent prostate tissue. In contrast to heredit ary nonpolyposis colorectal cancer, characterized by defects predominantly in MLH1 and MSH2, the samples we examined showed more tumor foci with loss of PMS1 and PMS2. PMS1, which is only expressed in the basal cells in norma l glands, is conspicuously absent in most prostate cancer. From these resul ts, we conclude that there are defects of MMR genes in human prostate cance r.