Effect of energy restriction on the expression of cyclin D1 and p27 during premalignant and malignant stages of chemically induced mammary carcinogenesis.

The restriction of energy intake has a profound inhibitory effect on carcinogenesis, yet the mechanism or mechanisms that account for this effect are unknown. In this experiment, the hypothesis tested was that energy restriction upregulates the expression of p27/kip1, a gene product associated with cell-cycle growth arrest, while downregulating cyclin D1, a protein that combines with cyclin-dependent kinases to promote phosphorylation of retinoblastoma protein and the progression of cells through the cell cycle. We studied levels of these proteins in uninvolved mammary epithelial cells and in mammary intraductal proliferations, ductal carcinomas in situ, and adenocarcinomas induced in response to administration of 1-methyl-1-nitrosourea in animals fed either ad libitum or 90%, 80%, or 60% of ad libitum intake. Protein levels were evaluated immunohistochemically by using computer-assisted image analysis to quantify differences in protein expression among treatment groups. The expression of p27 increased and the expression of cyclin D1 decreased dose-dependently in response to energy restriction. The effect was greater on p27 than on cyclin D1. The hypothesis proposed is that energy restriction inhibits carcinogenesis by arresting cell-cycle progression by regulating p27/kip1.