PREVENTION MODELS

类维生素A经典地与细胞的分化有关， 上皮样起源的细胞， 发展与此一致，初步结果表明， 维甲酸诱导分化、生长抑制 以及基于钙粘蛋白的细胞膜的组分的功能表达 乳腺癌细胞的粘附和信号系统。E-钙粘蛋白丢失 和/或钙粘蛋白相关分子的缺陷， 乳腺肿瘤进展。拟议工作的一个目标是澄清 钙粘蛋白在类维生素A作用中的作用。 我们已经确定了钙粘蛋白相关分子β-连环蛋白， 是乳腺癌细胞对类维生素A反应的关键因素。贝塔- 连环蛋白被认为不仅在以钙粘蛋白为基础的细胞间 粘附以及细胞内信号传导。初步结果 证明β-连环蛋白是酪氨酸和 丝氨酸/苏氨酸激酶和β-连环蛋白作为复合物存在， 丝氨酸/苏氨酸激酶和肿瘤抑制基因APC。另一个目标 这项建议的目的是研究丝氨酸激酶活性在 乳腺癌细胞对类维生素A的反应视黄醛衍生物和 抗雌激素如他莫昔芬也被提议作为 乳腺癌的化学预防剂。初步结果在一 首次建立了乳腺癌动物模型， 9-顺式视黄酸，RXR类的天然配体， 类维生素A受体，可以显着降低肿瘤的发病率和肿瘤 负担重要的是，与他莫昔芬，9-顺式维甲酸， 显著延长肿瘤潜伏期，进一步降低肿瘤发生率 和数量，并增加无肿瘤动物的数量。一个重要 这项工作的目标是使用一些其他的动物模型 乳腺癌的发生，以确认9-顺式的化学预防作用 视黄酸和与他莫昔芬的协同作用。我们计划优化 在这些动物模型中的化学预防策略 在人类中进行的类维生素A和他莫昔芬联合化学预防试验。 尽管该建议强调了类维生素A在治疗中的效用， 化学预防，维甲酸治疗抑制了许多明显的生长， 恶性乳腺癌细胞结合以下能力， 类维生素A治疗增加钙粘蛋白依赖性细胞间粘附 数据表明，类维生素A可能是有用的，不仅在预防 乳腺癌，而且在其治疗我们的最终目标是使用 2期临床试验的材料，以确定分子和 细胞标记物与，并可能预测 对类维生素A和类维生素A/他莫昔芬联合治疗的反应性。

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.