Abstract A36: Resveratrol decreases DNMTs in a human relevant animal model of breast cancer

Background: We previously reported that trans-resveratrol (resveratrol) downregulates the expression DNA methyltransferases (DNMTs) 1 and 3b in vitro and demethylates the tumor suppressor gene RASSF-1a in the breasts of women who are at increased breast cancer risk. Effects increased with increasing dose/circulating level of the agent, respectively. In the current report, we evaluated the effect of increasing doses of resveratrol on mammary tumor formation in the ACI rat, which develops estrogen dependent mammary carcinoma. Methods: 91 female rats were treated with a slow release estradiol (E2) pellet plus one of the following: 5 mg/kg/day (low dose) resveratrol (n=23), 25 mg/kg/day (high dose) resveratrol (n=22), 0.1mg/kg/week 5-azacytadine (aza) (n=22), an inhibitor of DNMTs which is used clinically, or control (n=24). The animals were examined weekly to assess for the presence of tumor formation. After 5.5 months of treatment, the animals were sacrificed and the mammary glands harvested, with half of each gland snap frozen and the other half formalin fixed. Specimens were evaluated by a board certified pathologist to confirm histology as benign or malignant. DNMT1 and 3b were measured by qRT-PCR. Results: Tumor formation was lowest (18% of rats) in the high dose resveratrol and 5-aza groups, intermediate in the low dose resveratrol group (26%) and highest in control (33%). DMNT1 expression was significantly (p<0.0001) influenced by treatment, while DNMT3b was not. On the other hand, DNMT3b expression was significantly (p<0.0001) influenced by histology (benign vs. malignant), whereas DNMT1 was not. Conclusion: Treatment with resveratrol and 5-aza significantly influence DNMT expression, which may be important in the prevention/delay of mammary tumor formation. This mechanism of action of resveratrol warrants further investigation. Citation Format: Wenyi Qin, Weizhu Zhu, Ke Zhang, Kaitlin Clarke, Edward R. Sauter. Resveratrol decreases DNMTs in a human relevant animal model of breast cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A36.