Chemoprevention of Breast Cancer, Proteomic Discovery of Genistein Action in the Rat Mammary Gland

Author: Craig Rowell, D. Mark Carpenter and Coral A. Lamartiniere.
Publication: Journal of Nutrition, 135:2953S-2959S, December 2005.

It is estimated that three-fourts of all cancer deaths are related to lifestyle factors, including food. Exposure of our body tissues to chemicals at the time of their formation and maturation could have an effect of cancer risk during adulthood. Studies with rats have showed that the consumption of foods rich in isoflavones during the prepubertal period suppresses chemically induced mammary cancers. The main isoflavone, which is responsible for this action, is genistein. Consumption of the isoflavone genistein during the adult phase does not offer this protection against mammary gland cancer.

The proteomic method was used to investigate the effect of genistein on chemically (DMBA) induced mammary gland cancer. Rats were injected with genistein when they were 16, 18 and 20 days old. When the rats were 21 days the mammary glands were investigated. The proteins in the mammary glands were measured with 2-D gels. The protein GTP-cyclohydrolase 1 and tyrosine hydroxylase were significantly increased, whereas vascular endothelial growth factor receptor 2 was significantly reduced in the rats treated with the isoflavone genistein. GTP-cyclohydrolase 1 is known to interfere with the production of BH4 which stimulates amino acid hydroxylases and nitric acid synthases. Inhibition of the vascular endothelial growth factor receptor 2 is known to prevent DMBA induced mammary gland cancer.

Prepubertal exposure to genistein makes the mammary gland of adult rats cells less proliferative and less susceptible to cancer. The exposure of mammary gland cells to genistein during prepuberty increases cell proliferation and gland maturation. As a result the mammary gland shows fewer terminal end buds and more lobules. The terminal end buds are the most susceptible to chemical carcinogens.

In order to determine of the effect of genistein on the mammary gland was related to its estrogenic action, test were done with daidzein (another isoflavone with estrogenic action) and the estrogen estradiol. It was found that daidzein and estradiol did not produce significant changes in the protein composition of the mammary gland, indicating that a specific non-estrogenic property of genistein was responsible for the chemopreventive action of genistein.

The study concluded that early prepubertal exposure of the mammary gland to genistein enhances cell proliferation and maturation making them less susceptible to chemically induced cancer of the mammary gland.