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RFA CA-03-016:
Diet, DNA Methylation and Other Epigenetic Events, and Cancer Prevention

Altered Breast Methylation after Low/Hi Dose Isoflavones

Principal Investigator: Sauter, Edward R
Institution: University of Missouri Columbia
NCI/DCP Program Director: Ross, Sharon A
Project ID (Grant #): 1R21CA105330-01
RFA/PA Number: RFA-CA-03-016
Project Funding Period: 05/28/2004 to 04/30/2006

Description (provided by applicant)

DNA methylation is a vital process in normal development and in cancer. Most cancers demonstrate whole genomic hypomethylation and promoter hypermethylation in certain critical tumor suppressor and growth regulatory genes, which leads to genetic instability. There is growing evidence that nutraceuticals can influence gene expression through DNA methylation. Dietary methyl donors such as folic acid are known to affect DNA methylation, and numerous studies indicate that a diet deficient in methyl donors is associated with an increased breast cancer risk. The isoflavones genistein and daldzein, which are present in soy and other foods, have a chemical structure similar to estrogen and have weak estrogenic activity. We have used differential methyl hybridization (DMH) microarray analysis to demonstrate that the isoflavone genistein leads to hypermethylation in the prostate, which like the breast is an hormonally responsive organ. The effects of isoflavones on the breast are controversial. There is increasing evidence that the predominant effect is related to the dose ingested. We propose a randomized trial, using a double blind, 2-arm parallel design. We elected to study two isoflavones doses (40 mg/d isoflavone, low dose; 150 mg/d, high dose), because preclinical and clinical research has suggested that these doses led to a different effect on the breast, with the low dose being stimulatory and the high dose inhibitory. Premenopausal women will receive the isoflavones genistein and daldzein in capsule form for one menstrual period, with nipple aspirate fluid (NAF), blood and ductoscopic samples collected before starting and after finishing isoflavone ingestion. We will evaluate delivery to the breast of low or high dose isoflavones by measuring isoflavone levels in NAF, as well as systemic delivery by measuring isoflavone levels in the blood. We will perform DMH microarray and cytologic analyses on breast ductal samples collected using ductoscopy, which provides a cellular, targeted sample from a chosen breast duc. The findings will provide information on isoflavone delivery to the breast based on dose ingested, as well as the effects of ingestion of a low or high dose isoflavone preparation on methylation and breast cellular morphology.

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