Dietary Isoflavones, Tamoxifen, and Tumor Growth

说明(申请人提供)：乳腺癌的风险随着年龄的增长而增加，大多数乳腺癌对雌激素(E)敏感。大约75%患有乳腺癌的女性年龄在50岁以上。因此，大多数患有乳腺癌的女性都是绝经后。如果一名妇女患有对E敏感的乳腺癌，她很可能正在接受抗雌激素他莫昔芬()治疗。相当多的研究集中在E反应乳腺癌妇女使用激素替代疗法(HRT)，大多数肿瘤学家/内科医生不建议这些妇女使用HRT。然而，绝经后乳腺癌妇女对大豆和雌激素异黄酮类的摄入量急剧增加，被认为是HRT的一种天然和安全的替代品。这种用饮食中的雌激素异黄酮来缓解更年期和相关的更年期症状的“自我用药”，往往是在医生不知情的情况下进行的。雌激素异黄酮类饮食对E反应乳腺癌女性患者的安全性，以及这些植物雌激素否定疗法有效性的可能性是一个尚未得到充分评估的潜在风险。我们的初步结果表明，膳食中的染料木素，大豆和含大豆异黄酮类补充剂中的主要异黄酮类，可以否定/压倒对E刺激的裸鼠肿瘤生长的抑制作用。在我们提出的实验中，我们将确定金雀异黄素可以否定/压倒的抑制作用的最低饮食剂量。此外，30%-40%的女性食用异黄酮会在大肠内通过肠道新陈代谢产生马醇。这种雌激素代谢物可以增加饮食中的雌激素负荷，并有可能增加食用异黄酮类药物的女性(马匹生产者)的乳腺癌nsk。我们已经开发出一种经济有效的方法将芒柄花素转化为马醇，用于体外和体内的肿瘤生长研究。这将使我们第一次能够评估木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来否定/压倒对E刺激的肿瘤生长的抑制作用。综上所述，我们的研究将确定生理相关饮食剂量的雌激素异黄酮类和代谢物是否可以否定/压倒对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.