2000 WHRG Grant Program

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Breast Cancer Prevention by Resveratrol

Minglin Li, Ph.D.
School of Medicine, University of Maryland, Baltimore

Breast cancer affects one out of eight American women. Preventive therapy is becoming increasingly important in fighting this disease. Tamoxifen and raloxifene are among the most intensively investigated agents for prevention of breast cancer. This proposal is design to explore the potential of resveratrol as chemopreventive agent against breast cancer. Resveratrol (3,4,5'-trihydroxy-trans-stilbene) is a natural product present in red wine and a variety of human foods and marketed worldwide in combination with multivitamin components. It is believed that resveratrol is the responsible component for the beneficial effect of moderate consumption of red wine on heart. Its inhibitory effects on proliferation of a variety of cells including breast cancer cells suggests that resveratrol could be a potent cancer preventive agent. This preventive effect of resveratrol on breast cancer has not been studied in vivo. The WAP-TAg mice, a transgenic mouse model of breast cancer progression, will be used to conduct this proposal. In the WAP-TAg mice, the tumorigenesis is primarily dependent on the ability of SV40 large T antigen (TAg) to inactivate the function of tumor suppressor gene p53 and Rb. P53 and Rb mutations account for a significant portion of human breast cancers. This model has being used to test tumor prevention efficacy of some agents such as DFMO.

In this proposal the following two specific aims will be approached. The working hypothesis for this proposal is resveratrol can delay tumor onset and reduce tumor multiplicity and incidence. This effect of resveratrol results from inhibition of cell proliferation or apoptosis by regulation of function of certain genes.

Specific Aim 1: Determine whether resveratrol can prevent or delay tumor formation. The goal of this specific aim is to detect the efficacy and toxicity of resveratrol. To conduct this aim different doses of resveratrol will be given orally to WAP-TAg mice after the tumorigenic process is initiated by developmentally and hormonally controlled expression of TAg in mammary glands. Palpable and visible tumors will be observed. The mice will be euthanized after they have reached the age of 210 days at which most WAP-TAg mice develop tumors without treatment. The multiplicity (tumors/mouse) and incidence of tumors will be recorded and the abnormalities of the major organs with the emphasis of ovary will be examined.

Specific Aim 2: Determine whether resveratrol can affect cell proliferation, apoptosis and expression of genes associated with cell proliferation and apoptosis. The goal of this specific aim is to investigate the possible mechanism of resveratrol on growth of preneoplastic mammary epithelial cells and determine the endpoint surrogate biomarkers. WAP-TAg mice exposed to resveratrol will mate and be euthanized after one month treatment with resveratrol. Mammary tissue will be collected for analysis of cell proliferation, apoptosis and gene expression.

This proposed in vivo study is designed to further establish the potential application of resveratrol as a breast cancer preventive agent and establish an in vivo model to study the underlying molecular mechanism. The long-term goal of this study is to provide information for the clinical trials and the eventual use of resveratrol as chemopreventive drug to human breast cancer.