PREVENTION MODELS

类维A酸类化合物经典地被认为与分化的 上皮样起源的细胞，并在 发展。与此一致，初步结果表明 维甲酸诱导分化与生长抑制的关系 以及钙粘附素基组分的功能表达 乳腺癌细胞的黏附和信号传递系统。E-钙粘附素的丢失 和/或钙粘附素相关分子的缺陷被认为与 乳腺肿瘤进展。拟议工作的一个目标是澄清 基于钙粘附素的黏附和信号转导在维甲酸作用中的作用。 我们已经确定钙粘素相关分子β-连环蛋白是 乳腺癌细胞对维甲酸的反应中的关键因素。测试版- 连环蛋白被认为不仅在基于钙粘附素的细胞中起作用 黏附也存在于细胞内的信号传递中。初步结果 证明β-连环蛋白是酪氨酸和酪氨酸的底物 丝氨酸/苏氨酸激酶和β-连环蛋白以与 丝氨酸/苏氨酸激酶和肿瘤抑制基因APC。另一个目标 这一建议的目的是研究丝氨酸激酶活性在 乳腺癌细胞对维甲酸的反应。维甲酸和维甲酸 抗雌激素，如他莫昔芬，也被提出为 乳腺癌的化学预防药物。初步结果合一 首次建立了乳腺癌发生的动物模型 9-顺式维甲酸，RXR类的天然配体 视黄酸受体，可显著降低肿瘤发病率和肿瘤 负担。重要的是，与他莫昔芬联合使用，9-顺式维甲酸 显著延长肿瘤潜伏期，进一步降低肿瘤发病率 和数量，并增加无肿瘤动物的数量。一个重要的 拟议工作的目标将是使用一些其他动物模型 以证实9-顺的化学预防作用 维甲酸及其与他莫昔芬的协同作用。我们计划优化 这些动物模型在启动前的化学预防策略 维甲酸和他莫昔芬联合应用于人体的化学预防试验。 尽管这项提议强调了维甲酸在 化学预防，维甲酸治疗明显抑制了许多人的生长 恶性乳腺癌细胞。与……能力结合在一起 维甲酸治疗增加钙粘附素依赖的细胞间黏附 数据表明，类维甲酸可能是有用的，不仅在预防 乳腺癌，而且在它的治疗上我们的最终目标是用 来自2期临床试验的材料以鉴定分子和 与之相关并可预测的细胞标志物 对维甲酸和维甲酸/他莫昔芬联合治疗的反应。

Retinoids have classically been associated with the differentiation of cells of epithelioid origin and with pattern formation during development. Consistent with this, preliminary results demonstrate a relationship among retinoid-induced differentiation, growth inhibition and the functional expression of components of the cadherin-based adhesion and signalling system in breast cancer cells. Loss of E-cadherin and/or defects in cadherin-associated molecules have been implicated in breast tumor progression. It is one goal of the proposed work to clarify the role of cadherin based adhesion and signalling in retinoid action. We have identified the cadherin-associated molecule beta-catenin as being a key element in the breast cancer cell response to retinoids. Beta- catenin is thought to function not only in cadherin-based cell-cell adhesion but also in intracellular signalling. Preliminary results demonstrate that beta-catenin is a substrate for both tyrosine and serine/threonine kinases and that beta-catenin exists as a complex with a serine/threonine kinase and the tumor suppressor gene APC. Another goal of this proposal is to investigate the role of serine kinase activity in the response of breast cancer cells to retinoids. Retinoids and antiestrogens such as tamoxifen have also been proposed as chemopreventive agents in breast cancer. Preliminary results in one animal model of mammary carcinogenesis demonstrate for the first time that 9-cis retinoic acid, the natural ligand for the RXR class of retinoid receptors, can significantly decrease tumor incidence and tumor burden. Importantly, in combination with tamoxifen, 9-cis retinoic acid significantly extends tumor latency, further decreases tumor incidence and number, and increases the number of tumor free animals. An important goal of the proposed work will be To use a number of other animal models of mammary carcinogenesis to confirm the chemopreventive effects of 9-cis retinoic acid and synergy with tamoxifen. We plan to optimize chemoprevention strategies in these animal models prior to initiating combined retinoid and tamoxifen chemoprevention trials in humans. Although this proposal emphasizes the utility of retinoids in chemoprevention, retinoid treatment inhibits the growth of many overtly malignant breast cancer cells. Taken together with the ability of retinoid treatment to increase cadherin-dependent cell-cell adhesion thee data suggest that retinoids may be useful, not only in the prevention of breast cancer, but also in its treatment Our final goal is to use material from the phase 2 clinical trial to identify molecular and cellular markers which are associated with, and which may predIct responsiveness to, retinoid and combined retinoid/tamoxifen treatment.