Progression of cells to a metastatic phenotype begins in the primary organ and represents an important chemoprevention target. In preclinical studies, genistein induces reversion of human prostate cancer (PCa) cells to a less metastatic phenotype. In a phase II study, men with localized PCa were randomized between genistein treatment versus not prior to radical prostatectomy. Analysis of prostate epithelial cells within harvested organs revealed that genistein had the following effects: 1) it decreased matrix metalloproteinase 2 (MMP-2) expression; 2) it induced nuclear spreading; a surrogate marker of inhibition of cell detachment; and 3) gene expression profiling demonstrated selective modulation of genes associated with regulation of cell motility in other cell types. By engineering the expression of these genes in cell lines, we demonstrated that they were important regulators of human PCa cell invasion. Genistein increased the expression of genes that suppress invasion and decreased the expression of genes that enhance invasion. Together, this study demonstrates that genistein induces reversion of human prostate cells in man to a less metastatic phenotype. Importantly, this study demonstrates the proof-of-principal concept that the conduct of molecular screens in human chemoprevention trials has the ability to identify the mechanism of action of investigational agents.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN02-04.