Resveratrol Suppresses Breast Cancer Formation

Early laboratory research has shown that resveratrol, a common dietary supplement, suppresses the abnormal cell formation that leads to most types of breast cancer, suggesting a potential role for the agent in breast cancer prevention. Resveratrol is a natural substance found in red wine and red grapes.

“Resveratrol has the ability to prevent the first step that occurs when estrogen starts the process that leads to cancer by blocking the formation of the estrogen DNA adducts. We believe that this could stop the whole progression that leads to breast cancer down the road,” said Eleanor G. Rogan, Ph.D., a professor in the Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska Medical Center.

Rogan was the lead author of the report that was published in the July 2008 issue of Cancer Prevention Research, a journal of the American Association for Cancer Research.

For the current study, Rogan and colleagues measured the effect of resveratrol on cellular functions known to contribute to breast cancer.

The formation of breast cancer is a multi-step process which differs depending on type of disease, a patient’s genetic makeup and other factors. However, scientists know that many breast cancers are fueled by increased estrogen, which collects and reacts with DNA molecules to form adducts. Rogan and colleagues found that resveratrol was able to suppress the formation of these DNA adducts.

“This is dramatic because it was able to be done with fairly low concentrations of resveratrol to stop the formation of these DNA adducts in the cells we studied,” said Rogan. Although researchers experimented with up to 100 µmol/L of resveratrol, the suppression of DNA adducts was seen with 10 µmol/L. A glass of red wine from hand-crafted production contains between 9 and 28 µmol/L of resveratrol.

The researchers also found that resveratrol suppressed the expression of CYP1B1 and the formation of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, two known risk factors for breast cancer.

Rogan said resveratrol works by inducing an enzyme called quinone reductase, which reduces the estrogen metabolite back to inactive form. By making estrogen inactive, resveratrol decreases the associated risk.

The current study was conducted in laboratory cultures, and will need to be confirmed in larger human trials, Rogan said.

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 28,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and 80 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication and its sixth major journal, Cancer Prevention Research, is dedicated exclusively to cancer prevention, from preclinical research to clinical trials. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.

Abstract

Exposure to estrogens is a risk factor for breast cancer. Specific estrogen metabolites may initiate breast cancer and other cancers. Genotoxicity may be caused by cytochrome P450 (CYP)–mediated oxidation of catechol estrogens to quinones that react with DNA to form depurinating estrogen-DNA adducts. CYP1B1 favors quinone formation by catalyzing estrogen 4-hydroxylation, whereas NAD(P)H quinone oxidoreductase 1 (NQO1) catalyzes the protective reduction of quinones to catechols. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1B1 expression through the aryl hydrocarbon receptor (AhR). Resveratrol has anticancer effects in diverse in vitro and in vivo systems and is an AhR antagonist that decreases CYP expression but induces NQO1 expression. The chemopreventive effect of resveratrol on breast cancer initiation was investigated in MCF-10F cells. Its effects on estrogen metabolism and formation of estrogen-DNA adducts were analyzed in culture medium by high-performance liquid chromatography, whereas its effects on CYP1B1 and NQO1 were determined by immunoblotting and immunostaining. The antitransformation effects of resveratrol were also examined. TCDD induced expression of CYP1B1 and its redistribution in the nucleus and cytoplasm. Concomitant treatment with resveratrol dose-dependently suppressed TCDD-induced expression of CYP1B1, mainly in the cytoplasm. Resveratrol dose- and time-dependently induced expression of NQO1. NQO1 is mainly in the perinuclear membrane of control cells, but resveratrol induced NQO1 and its intracellular redistribution, which involves nuclear translocation of nuclear factor erythroid 2–related factor 2. Resveratrol decreased estrogen metabolism and blocked formation of DNA adducts in cells treated with TCDD and/or estradiol. Resveratrol also suppressed TCDD and/or estradiol-induced cell transformation. Thus, resveratrol can prevent breast cancer initiation by blocking multiple sites in the estrogen genotoxicity pathway.

Source:

Fang Lu, Muhammad Zahid, Cheng Wang, Muhammad Saeed, Ercole L. Cavalieri and Eleanor G. Rogan. Resveratrol Prevents Estrogen-DNA Adduct Formation and Neoplastic Transformation in MCF-10F Cells. Cancer Prevention Research 1, 135-145, July 1, 2008. doi: 10.1158/1940-6207.CAPR-08-0037.

Key concepts: breast cancer, resveratrol, chemoprevention