Dietary Isoflavones, Tamoxifen, and Tumor Growth

描述（由申请人提供）：乳腺癌的风险随着年龄的增长而增加，大多数乳腺癌是雌激素(E)反应性的。大约75%的乳腺癌患者年龄在50岁以上。因此，大多数患乳腺癌的妇女是绝经后的。如果一名女性患有e反应性乳腺癌，她很可能正在接受抗雌激素他莫昔芬（TAM）治疗。相当多的研究集中在e反应性乳腺癌妇女使用激素替代疗法（HRT），大多数肿瘤学家/医生不建议这些妇女使用HRT。然而，患有乳腺癌的绝经后妇女将大豆和雌激素异黄酮作为替代激素替代疗法的一种天然且被认为“安全”的选择，其消费量急剧增加。这种通过膳食雌激素异黄酮来缓解更年期和tam相关的绝经样症状的“自我用药”通常是在医生不知情的情况下进行的。对于患有e反应性乳腺癌的妇女，膳食雌激素异黄酮的安全性以及这些植物雌激素可能会抵消TAM治疗的有效性，这是一种潜在的风险，尚未得到充分的评估。我们的初步结果表明，在大豆和含有异黄酮的补充剂中，膳食染料木黄酮（genestein）是主要的异黄酮，它可以抵消/压倒TAM对e刺激的胸腺小鼠肿瘤生长的抑制作用。在我们提出的实验中，我们将确定可以抵消/压倒TAM抑制作用的染料木素的最小膳食剂量。此外，30-40%摄入异黄酮的女性可以通过大肠内的肠道代谢产生雌马酚。这种雌激素代谢物会增加饮食中雌激素的负荷，并可能增加摄入异黄酮的女性（雌酚产生者）患乳腺癌的风险。我们已经开发出一种经济有效的方法，将刺芒柄花素转化为马酚，用于体外和体内肿瘤生长研究。这将使我们第一次有能力评估雌马酚与染料木素的相互作用，并确定这是否增加了足够的雌激素活性，以抵消/压倒TAM对e刺激肿瘤生长的抑制作用。总之，我们的研究将确定在生理上相关的膳食剂量下，饮食中的雌激素异黄酮和代谢物是否可以抵消/压倒TAM对e刺激的乳腺癌生长的抑制作用。

DESCRIPTION (provided by applicant): 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.