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Defects of DNA mismatch repair in human prostate cancer
1Laboratory of Cancer Genomics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Abstract:
Loss of mismatch repair (MMR) function leads to the accumulation of errors that normally occur during DNA replication, resulting in genetic instability. Germ-line mutations of MMR genes in the patients with hereditary nonpolyposis colorectal cancer lead to inactivation of MMR protein functions, and the defects of MMR are well correlated to the high rate of microsatellite instability in their tumors. Previous studies (T. Uchida, et al. Oncogene, 10: 1019-1022, 1995; S. Egawa, et al. Cancer RES:, 55: 2418-2421, 1995; J. M. Cunningham, et al. Cancer RES:, 56: 4475-4482, 1996; X. Gao, et al. Oncogene, 9: 2999-3003, 1994; H. Rohrbach, et al. Prostate, 40: 20-27, 1999) have shown that genetic instability (chromosomal and microsatellite instability) is detectable in human prostate cancer. To elucidate the role of MMR genes in the tumorigenesis of prostate cancer, we evaluated the expression of these genes in human cancer cell lines and in tumor specimens. Using Western blot analysis, we detected loss among MSH2, MLH1, PMS2, and PMS1 proteins in DU145, LNCaP, p69SV40T, M2182, and M12 cells. In addition, genomic instability in the prostate cell lines including DU145, PC3, LNCaP, p67SV40T, M2182, and M12 was detected by a microsatellite mutation assay. Significantly, immunohistochemical analysis of prostatic tissue revealed the reduction or absence of MMR protein expression in the epithelium of prostate tumor foci compared with normal adjacent prostate tissue. In contrast to hereditary 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 normal glands, is conspicuously absent in most prostate cancer. From these results, we conclude that there are defects of MMR genes in human prostate cancer.
Insights
Defects in mismatch repair (MMR) genes, crucial for DNA replication accuracy, are linked to prostate cancer development. Loss of MMR proteins, particularly PMS1 and PMS2, was observed in prostate tumors, indicating their role in cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Loss of mismatch repair (MMR) function causes DNA replication errors and genetic instability.
- MMR gene defects are implicated in hereditary nonpolyposis colorectal cancer, correlating with microsatellite instability.
- Genetic instability, including microsatellite instability, is present in human prostate cancer.
Purpose of the Study:
- To investigate the role of mismatch repair (MMR) genes in prostate cancer tumorigenesis.
- To evaluate MMR gene expression in human prostate cancer cell lines and tumor specimens.
Main Methods:
- Western blot analysis to detect MMR protein expression (MSH2, MLH1, PMS2, PMS1) in prostate cancer cell lines.
- Microsatellite mutation assay to assess genomic instability in prostate cell lines.
- Immunohistochemical analysis of prostatic tissue to compare MMR protein expression in tumor foci versus normal adjacent tissue.
Main Results:
- Loss of MSH2, MLH1, PMS2, and PMS1 proteins was detected in various prostate cancer cell lines.
- Genomic instability was confirmed in prostate cancer cell lines.
- Prostate tumor tissues showed reduced or absent MMR protein expression compared to normal tissues.
- Loss of PMS1 and PMS2 was more prevalent in prostate tumors than MLH1 and MSH2 defects.
- PMS1 expression was notably absent in most prostate cancers, while normally present in basal cells.
Conclusions:
- Defects in mismatch repair (MMR) genes are present in human prostate cancer.
- Loss of MMR protein expression, particularly PMS1 and PMS2, is associated with prostate cancer.
- MMR gene defects contribute to the genetic instability observed in prostate cancer development.