title: Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer.
abstract: Trans-resveratrol, present in high concentration in the skin of red grapes and red wine, has a dose-dependent antiproliferative effect in vitro, prevents the formation of mammary tumors, and has been touted as a chemopreventive agent. Based upon in vitro studies demonstrating that trans-resveratrol downregulates the expression of 1) DNA methyltransferases and 2) the cancer promoting prostaglandin (PG)E(2), we determined if trans-resveratrol had a dose-related effect on DNA methylation and prostaglandin expression in humans. Thirty-nine adult women at increased breast cancer risk were randomized in double-blind fashion to placebo, 5 or 50 mg trans-resveratrol twice daily for 12 wk. Methylation assessment of 4 cancer-related genes (p16, RASSF-1α, APC, CCND2) was performed on mammary ductoscopy specimens. The predominant resveratrol species in serum was the glucuronide metabolite. Total trans-resveratrol and glucuronide metabolite serum levels increased after consuming both trans-resveratrol doses (P < .001 for both). RASSF-1α methylation decreased with increasing levels of serum trans-resveratrol (P = .047). The change in RASSF-1α methylation was directly related to the change in PGE(2) (P = .045). This work provides novel insights into the effects of trans-resveratrol on the breast of women at increased breast cancer risk, including a decrease in methylation of the tumor suppressor gene RASSF-1α. Because of the limited sample size, our findings should be validated in a larger study.
authors.affiliation: Departments of Surgery and Pathology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, USA.
authors.forename: Weizhu
authors.initials: W
authors.lastname: Zhu
authors.forename: Wenyi
authors.initials: W
authors.lastname: Qin
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: George E
authors.initials: GE
authors.lastname: Rottinghaus
authors.forename: Yin-Chieh
authors.initials: YC
authors.lastname: Chen
authors.forename: Beth
authors.initials: B
authors.lastname: Kliethermes
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sauter
mesh_terms: D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000517:prevention & control*; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D000077185:Resveratrol; D012307:Risk Factors; D013267:Stilbenes / Q000097:blood / Q000627:therapeutic use*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C080336:CCND2 protein, human; D056742:Cyclin D2; C411762:RASSF1 protein, human; D013267:Stilbenes; D025521:Tumor Suppressor Proteins; D015232:Dinoprostone; D000077185:Resveratrol