Relevance of cyclin D1 and other molecular markers to cancer chemoprevention.

Until recently studies on mutations in cellular genes implicated in multistage carcinogenesis have concentrated mainly on dominant acting mutations in cellular proto-oncogenes, genes that normally mediate agonist-induced signal transduction pathways, and recessive mutations in cellular tumor suppressor genes, whose normal products appear to inhibit cell growth and/or control differentiation and cell-cell interactions. It seems likely, however, that a third category of cellular genes, the cyclins and cyclin-related genes, may also be critical targets during multistage carcinogenesis because of the central role that they play in controlling cell cycle progression. These proteins could, therefore, provide biomarkers for identifying individuals at high risk of developing cancer and also serve as novel targets for chemopreventive agents. This paper reviews evidence that the gene cyclin D1 is amplified and/or overexpressed in a major fraction of human tumors, and that this can occur relatively early in the carcinogenic process. Mechanistic studies indicates that this overexpression plays a critical role in tumor progression as well as the maintenance of the tumorigenic phenotype. Thus, increased cyclin D1 expression can enhance gene amplification and cell transformation and antisense to cyclin D1 can revert malignant cells. The latter findings provide direct evidence that cyclin D and related proteins might be useful markers and also targets for cancer chemoprevention.