Overexpression of cyclin E protein is closely related to the mutator phenotype of colorectal carcinoma

Abstract

Background and aims: A subset of colorectal carcinomas are due to a deficiency in the DNA mismatch repair system. The molecular mechanisms of tumorigenesis in these tumors is not yet well understood. Deregulation of the cell cycle, specifically of the G₁ and S phases, is a hallmark of human cancers. Transition from the G₁ to the S phase is accelerated by increased cyclin E protein expression, and recent studies suggest that overexpression of cyclin E leads to chromosomal instability. The overexpression of cyclin E in a variety of human cancers, for example in colorectal, gastric, lung, breast, and kidney cancer, provides evidence that cyclin E plays a pivotal role in the cell cycle and replication. We examined whether the overexpression of cyclin E is related to the status of the mismatch repair system in colorectal carcinomas. Patients and methods: Frozen tumor samples and adjacent normal colon mucosa obtained from 100 patients were subjected to microsatellite analysis, RT-PCR, western blot analysis and immunohistochemistry. Results: High microsatellite instability was detected in 13 tumors, and in 10 of these (77%) cyclin E protein was overexpressed at least twofold compared to normal mucosa. In contrast, only 28 of the remaining 87 microsatellite stable tumors (32%) overexpressed cyclin E. Lower molecular weight cyclin E proteins were present in 7 of 87 microsatellite stable carcinoma (8%), compared to 7 cases exhibiting lower molecular weight isoforms of 13 MSI carcinoma (54%). Conclusion: Increased cyclin E protein expression and the appearance of lower molecular weight cyclin E proteins were significantly associated with MSI in colorectal tumors. The data indicate that increased and/or aberrant expression of cyclin E protein might contribute to the mutator phenotype of colorectal cancer.