Inhibition of xenoestrogen induced estrogen formation by chemopreventive phytochemicals

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Breast cancer is a leading cause of cancer-related death among American women. The American Cancer Society estimates 242,540 new cases and 40,910 deaths due to breast cancer in 2007. Xenoestrogens, which are present in the environment, includes polycyclic aromatic hydrocarbons (PAHs), and range from natural plant-derived phytoestrogens to man-made substances, such as pharmacologic agents and organochlorine pesticides. These chemicals share a common mode of action by activating the estrogen receptor (ER), and thereby elicit estrogenic responses. Xenoestrogens produce adverse health effects, such as reproductive dysfunction, developmental disorders, and proliferative disorders, including malignancies. The synthetic PAH, 3-Methylcholanthrene (3-MC) induces mammary tumors in rodents. The potent carcinogenic activity of 3-MC has led to its wide use as a prototype carcinogen in experimental animals. Estrogen plays a pivotal role in both the development and progression of breast cancer. CYP19 or aromatase mediates the conversion of the steroidal androgens to estrogens, which is the critical step in the biosynthesis of estrogens. The importance of estrogen makes aromatase and ER to be exceptional targets for the treatment and chemoprevention of breast cancer. Phytochemicals have the advantage of being dietary compounds that are less toxic to animals, abundant, and inexpensive.
 Studies in our laboratory revealed that in female mice treated with 7,12-dimethylbenz(a)anthracene (DMBA), the mammary EROD activities, CYP1A1, 1B1 and hepatic AHR mRNA expressions were increased significantly, when compared to controls. Significant reduction of these gene expressions along with elevation of several phase II enzymes were observed in female mice treated with chemopreventive phytochemicals, sulforaphane and curcumin. Our studies also show that in mammary tissues of mice exposed to 3-MC, EROD activities, CYP1A1 (phase I enzyme) and NQO1 (phase II enzyme) gene expressions increased when compared to controls. We also studied the efficacy of phytochemicals to reduce the gene expressions of aromatase and ER in female mice exposed to 3-MC, thus inhibiting estrogen formation.
 The knowledge gained from these studies will aid in the design of more highly developed and effective breast cancer prevention strategies and treatment of hormone-dependent tumors of the breast and uterus, involving dietary constituents.