The antitumor properties of the Merlot grape (and Merlot wine) polyphenols were evaluated in relation to their ability to modulate gene expression in developing tumors using an athymic nude mouse model transplanted with the estrogen receptor-negative MDA-MB231 cells. Groups of mice were fed a modified AIN 93G diet (Research Diets Inc, New Brunswick, NJ) with the experimental groups receiving 100 mg/kg body weight equivalent of polyphenols by gavage 3 times per week. After 1 week of acclimation and another week of polyphenol supplementation, MDA-MB231 cells were transplanted and the growth patterns of the tumors monitored. After 33 days of tumor growth, the animals were euthanized, the tumors isolated, and gene expression profiles analyzed using signal transduction and cell cycle arrays. The development of tumors was almost totally arrested in grape polyphenol-treated mice. Total polyphenols isolated from the wine were more effective in reducing tumor growth as compared with a hydrophobic polyphenol fraction isolated from the wine, showing a 50% and 60% reduction in tumor growth on day 33, respectively. Analysis of gene expression showed that genes such as CDK2, FAS, LEF1, PRKCE, and PTGS2, belonging to the NFkappaB, phospholipase C, and calcium signaling pathways, were down-regulated in tumors that developed in grape polyphenol-treated mice. Several genes related to cell cycle regulation, such as CDK5RAP1, RBBP8, and SERTAD1, were up-regulated in these tumors. Changes in the expression of these genes were less pronounced in tumors of wine polyphenol-treated mice. The study highlights the potential influences of dietary polyphenolic components on gene expression in estrogen receptor-negative tumors and its relation to inhibition of tumor growth.