Mammary cancer chemoprevention with the polyphenol resveratrol

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Despite recent advances in therapeutic treatments, breast cancer remains a serious disease and a leading killer among female cancers. More than 200,000 new cases of breast cancer and 40,000 deaths in 2005 have been estimated. There is, and should be, a strong effort to work toward the prevention of this disease. It is well accepted that environmental factors, especially diet and lifestyle, play a critical role in determining one’s risk for breast cancer. One dietary polyphenol that has received much attention for its health benefits, including anti-cancer properties, is resveratrol, a phytoalexin found in red grapes and red wine. We hypothesize resveratrol given in the diet can protect against chemically-induced mammary cancer through mechanisms that involve mammary gland differentiation and epithelial cell proliferation/apoptosis. Female Sprague Dawley rats were treated with 1000 mg resveratrol/kg AIN-76A diet from birth throughout life. At 50 days postpartum, animals were sacrificed to evaluate mammary whole mounts, cell proliferation, apoptosis, or treated with 60 mg dimethylbenz[a]anthracene (DMBA)/kg body weight to induce mammary adenocarcinomas. Tumor animals were palpated twice weekly for tumor appearance, location, and size. A follow-up tumor study with a lower dose of resveratrol (333 mg resveratrol/kg diet) was also done in the same manner. Gene expression arrays were done on mammary glands at 50 days postpartum for a further investigation of mechanisms of action. Both doses of resveratrol (1000 mg and 333 mg) were able to suppress mammary tumor multiplicity and increase tumor latency in a statistically significant manner. Mammary whole mount analysis revealed an increase in lobular structures, the least susceptible mammary terminal ductal structures to carcinogens. Cell proliferation and apoptosis assays revealed a drastic decrease in mammary epithelial cell proliferation and a significant increase in apoptosis in mammary terminal end buds, the most susceptible structures to carcinogenesis in the mammary gland. Microarray analysis at 50 days postpartum revealed 470 genes that were differentially regulated between the resveratrol-treated and control rats at a p value ≤ 0.01. Many of these genes confirmed or provide possible mechanisms to our findings on altered cell proliferation, apoptosis, and a reduction in carcinogenesis. Resveratrol treatment decreased several survival and cell cycle regulatory genes including Akt and several cyclin-dependent kinases. Also, resveratrol up-regulated the pro-apoptotic gene Bad and Metastasis Suppressor 1, while it down-regulated CYP1A1 and CYP1A2. We conclude that resveratrol in the diet can protect against mammary carcinogenesis by modulating mammary gland differentiation, and epithelial cell proliferation and apoptosis. (Supported by NIH-NCI-P20-CA93753, DAMD17-00-1-0119, and DOD-BC043793)