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，大多数患有乳腺癌的女性都是绝经后的。如果一个女人有E-反应性乳腺癌，很可能她正在接受抗雌激素他莫昔芬（TAM）治疗。相当多的研究集中在使用激素替代疗法（HRT）的妇女与E-反应性乳腺癌和大多数肿瘤学家/医生不建议HRT这些妇女。然而，作为HRT的天然和被认为“安全”的替代品，绝经后乳腺癌妇女的大豆和雌激素替代品消费量急剧增加。这种通过饮食雌激素类药物来缓解更年期和TAM相关的更年期样症状的“自我药疗”通常是在医生不知情的情况下进行的。饮食雌激素类雌激素对E-反应性乳腺癌女性的安全性以及这些植物雌激素否定TAM治疗有效性的可能性是一种尚未充分评估的潜在风险。我们的初步研究结果表明，膳食染料木素，主要存在于大豆和含黄酮的补充剂，可以否定/压倒TAM对E-刺激的肿瘤生长在无胸腺小鼠的抑制作用。在我们提出的实验中，我们将确定染料木黄酮的最小饮食剂量，可以否定/压倒TAM的抑制作用。此外，30-40%的服用雌马酮的女性可以通过大肠中的肠道代谢产生雌马酚。这种雌激素代谢物可以增加饮食中的雌激素负荷，并有可能增加女性（雌马酚生产者）的乳腺癌风险。我们已经开发了一种具有成本效益的方法，将芒柄花素转化为雌马酚，用于体外和体内肿瘤生长研究。这将使我们第一次能够评估雌马酚与染料木黄酮的相互作用，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刺激的肿瘤生长的抑制作用。总之，我们的研究将确定在生理学相关的饮食剂量下，饮食雌激素受体拮抗剂和代谢物是否可以否定/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.