CHEMOPREVENTION OF MAMMARY TUMORS BY TAMOXIFEN AND SOY

他莫昔芬作为ER α拮抗剂是一种有效的乳腺癌化学预防剂。大豆异黄酮染料木素和大豆苷元是ER（α和β）激动剂和拮抗剂。从理论上讲，大豆异黄酮可以增强或抵消他莫昔芬的化学预防作用。由于家族史而具有患乳腺癌的高风险的女性或具有ER+淋巴结的乳腺癌患者用他莫昔芬治疗5年，以分别预防乳腺癌或肿瘤转移。目前还不确定这些妇女是否因食用豆制品或服用植物雌激素作为补充剂而受益或受到伤害。我们最近在DMBA诱导的乳腺癌大鼠模型中的初步研究表明，大豆化合物增强了他莫昔芬的化学预防作用。然而，我们不知道这种增加的保护是否是由于他莫昔芬与大豆植物雌激素（染料木素和大豆苷元）的抗雌激素/抗增殖作用相结合，通过ER α介导。大豆植物雌激素可能通过与ER β结合来抑制肿瘤细胞增殖。或者，植物雌激素或其他大豆成分可以联合收割机将它们的抗氧化作用与他莫昔芬的抗氧化作用相结合，以提供增强的保护，防止肿瘤的发生或促进。我们推测，大豆含饮食将提高他莫昔芬的癌症化学预防作用的DMBA/乳腺癌大鼠模型。预测的作用机制是他莫昔芬作为ER α的拮抗剂（在乳腺中），染料木黄酮作为ER β的激动剂。我们将确定他莫昔芬和大豆的联合作用是否是由于这些药物的雌激素/抗雌激素作用，或者是由于它们的抗氧化作用。直接检验我们假设的具体目的是：（1）评价他莫昔芬与含大豆半粗提物或纯化大豆植物雌激素（染料木素和大豆苷元）的饲料对DMBA诱导的雌性大鼠乳腺癌发生的联合作用。(2)确定他莫昔芬和活性大豆成分之间预期的加和/协同化学预防作用的机制。

Tamoxifen as an ERalpha antagonist is an effective chemopreventive agent against breast cancer. The soy isoflavones genistein and daidzein are ER (alpha and beta) agonists and antagonists. Theoretically, soy isoflavones may enhance or may negate tamoxifen's chemopreventive effects. Women at high risk for developing breast cancer due to family history, or breast cancer patients with ER+ nodes, are treated with tamoxifen for 5 years to prevent breast cancer or tumor metastasis respectively. It is presently uncertain if these women are benefitted or harmed by consuming soy products, or by taking phytoestrogens as supplements. Our recent preliminary studies in the DMBA-induced mammary carcinogenesis rat model suggest that soy compound(s) enhance tamoxifen's chemopreventive action. However, we do not know if this increased protection is due to the antiestrogenic/antiproliferative effects of tamoxifen combined with those of soy phytoestrogens (genistein and daidzein) are mediated through ERalpha. It is possible that soy phytoestrogens may inhibit tumor cell proliferation by binding to the ERbeta. Alternatively, phytoestrogens or other soy ingredients may combine their antioxidant effects with those of tamoxifen to provide enhanced protection against tumor initiation or promotion. We hypothesize that soy-containing diets will enhance tamoxifen's cancer chemopreventive effects in the DMBA/mammary carcinogenesis rat model. The predicted mechanism of action is that tamoxifen acts as an antagonist with ERalpha (in the mammary gland) and genistein acts as an agonist with ERbeta. We will determine if the combined effect of tamoxifen and soy is due to the estrogenic/antiestrogenic effects of the agents, or due to their antioxidant effects. The specific aims designed to directly test our hypothesis are: (1) Evaluate the combined effects of tamoxifen with diets containing semi-crude extracts of soy or with purified soy phytoestrogens (genistein and daidzein) against DMBA induced mammary carcinogenesis in female rats. (2) Identify the mechanism of the anticipated additive/synergistic chemopreventive effect between tamoxifen and the active soy component.