Risk of breast increases with age and the majority of breast cancers are estrogen (E)-responsive. Approximately 75% of women with breast cancer are over 50 years old. Therefore, most women with breast cancer are postmenopausal. If a woman has E-responsive breast cancer it is likely that she is receiving antiestrogen tamoxifen (TAM) therapy. Considerable research has focused on the use of hormone replacement therapy (HRT) by women with E-responsive breast cancer and most oncologists/physicians do not recommend HRT to these women. However, there has been a dramatic increase in soy and estrogenic isoflavone consumption by postmenopausal women with breast cancer as a natural and perceived "safe" alternative to HRT. This "self-medication" with dietary estrogenic isoflavones for relief of menopausal and TAM-associated menopause-like symptoms is often done without their physician's knowledge. The safety of the dietary estrogenic isoflavones for women with E-responsive breast cancer and the potential for these phytoestrogens to negate the effectiveness of TAM therapy is a potential risk that has not been adequately evaluated. Our preliminary results indicate that the dietary genistein, the predominate isoflavone present in soy and isoflavone-containing supplements, can negate/overwhelm the inhibitory effects of TAM on E-stimulated tumor growth in athymic mice. In our proposed experiments, we will determine the minimum dietary dosage of genistein that can negate/overwhelm the inhibitory effects of TAM. Additionally, 30-40% of women consuming isoflavones can produce equol by enteric metabolism in the large intestine. This estrogenic metabolite can add to the dietary estrogen load and potentially increase breast cancer nsk in women (equol-producers) that consume isoflavones. We have developed a cost-effective method to convert formononetin to equol for use in both in vitro and in vivo tumor growth studies. This will allow us, for the first time, the ability to evaluate the interaction of equol with genistein and determine if this adds sufficient estrogenic activity to negate/overwhelm the inhibitory effects of TAM on E-stimulated tumor growth. In summary, our studies will determine if dietary estrogenic isoflavones and metabolites at physiologically relevant dietary dosages can negate/overwhelm the inhibitory effects of TAM on E-stimulated breast cancer growth.