CHEMOPREVENTION OF MAMMARY TUMORS BY TAMOXIFEN AND SOY

他莫昔芬作为ERα拮抗剂是一种有效的乳腺癌化学预防药物。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，大豆异黄酮会增强或抵消他莫昔芬的化学预防作用。有家族病史的高风险乳腺癌患者或有ER结节的乳腺癌患者，分别接受他莫昔芬5年的治疗，以防止乳腺癌或肿瘤转移。目前还不确定这些妇女通过食用大豆产品或服用植物雌激素作为补充剂是受益还是有害。我们最近在DMBA诱导的大鼠乳腺癌模型上的初步研究表明，大豆化合物(S)增强了他莫昔芬的化学预防作用。然而，我们不知道这种增强的保护作用是否是由于他莫昔芬和大豆植物雌激素(染料木素和大豆苷元)的抗雌激素/抗增殖作用是通过ERpha介导的。大豆植物雌激素可能通过与ERβ结合来抑制肿瘤细胞的增殖。或者，植物雌激素或其他大豆成分可以将它们的抗氧化作用与他莫昔芬的抗氧化作用结合起来，以增强对肿瘤启动或促进的保护。我们假设，在DMBA/乳腺癌大鼠模型中，含大豆的饮食将增强他莫昔芬的癌症化学预防作用。预测的作用机制是，他莫昔芬作为ERpha的拮抗剂(在乳腺中)，金雀异黄素作为ERbeta的激动剂。我们将确定他莫昔芬和大豆的联合作用是由于这两种药物的雌激素/抗雌激素作用，还是由于它们的抗氧化作用。旨在直接验证我们的假设的具体目的是：(1)评估他莫昔芬与含有半粗大豆提取物的饲料或含有精制大豆植物雌激素(染料木素和大豆苷元)的饲料对DMBA诱导的雌性大鼠乳腺癌的联合作用。(2)确定他莫昔芬和活性大豆成分之间预期的相加/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.