SELECTIVE RETINOIDS FOR BREAST CANCER THERAPY

维甲酸反应的多样性是在多个水平上介导的 在它们的信号通路中由三种维甲酸和维甲酸X 受体（RAR和RXR）亚型，由它们的 细胞分布模式的变化及其直接和间接 调节基因转录的机制。 因为如此 多样性，潜力高，效果更好，毒性更小 选择性类维生素A可用于治疗乳腺癌 每12名妇女中就有一名患有癌症。 p53突变 肿瘤抑制基因与生长抑制剂耐药性 类维生素A的作用与乳腺肿瘤的增加有关 恶性肿瘤和转移。 然而，我们已经确定了独特的 类维生素A，当与其他 类维生素A或干扰素或作为RAR/RXR泛激动剂发挥作用 或凋亡诱导剂抑制生长和克隆增殖 正常的类维生素A耐药乳腺癌细胞，不管他们的 p53状态。在这个程序项目（选择性维甲酸， 选择性维甲酸乳腺癌治疗），我们提出了一个 多学科的努力，涉及四个研究项目和一个 核心组件，以研究分子机制， 类维生素A对乳腺癌细胞发挥其抑制作用。的 由此产生的知识将使我们能够识别 治疗这种疾病的最佳候选人。 类视色素 维甲酸项目的设计和合成工作， 合成将为研究其作用机制提供必要的探针 生物评价的研究和候选人。 分子计划 维甲酸的作用机制将（1）研究RAR β如何 与β RARE相互作用或在乳腺癌中丢失，以及（2） 评估靶点诱导或抑制基因表达的能力， 转录。 类维生素A-受体相互作用项目将（1）研究 类维生素A诱导的RAR和RXR的构象变化， 单独的异二聚体或与类维生素A反应元件结合的异二聚体;（2）使用 体外转录系统，以评估调节 RAR β反应，和（3）表征类维生素A受体 6-[3-（1-金刚烷基）]-2-萘甲酸（AHPN）， 不依赖于类视色素受体诱导凋亡。 项目 乳腺癌中的细胞凋亡将（1）研究 乳腺AHPN凋亡活性示踪法研究AHPN的作用 癌细胞系和分离AHP受体;（2）评估 用于其对乳腺癌细胞的抑制活性的AHPN类似物 生长;和（3）对乳腺癌进行异种移植研究。 最佳类维生素A/AHPN类似物。生物测定核心将进行 (1)类维生素A受体结合研究，（2）血管生成测定，和 (3)药理学/毒理学/代谢评估，以协助 选择生物评价目标或用作机制的项目 用决策网络方法进行了探讨。

The diversity of the retinoid response is mediated at multiple levels in their signaling pathways by the three retinoic acid and retinoid X receptor (RAR and RXR) subtypes that is compounded by their variation in cell distribution patterns and their direct and indirect mechanisms for modulating gene transcription. Because of this diversity, the potential is high that more effective, less toxic selective retinoids can be identified for the treatment of breast cancer, which will afflict one woman in 12. Mutations in the p53 tumor suppressor genes and resistance to the growth inhibitory effects of retinoids are associated with increased breast tumor malignancy and metastasis. However, we have identified unique classes of retinoids that when used in combination with other retinoids or interferon or by functioning as RAR/RXR panagonists or inducers of apoptosis inhibit the growth and clonal proliferation of normally retinoid-resistant breast cancer cells, regardless of their p53 status. In this Program Project (Selective Retinoids for Selective Retinoids for Breast Cancer Treatment), we propose a multidiscriplinary effort involving four Research Projects and one Core Component to investigate the molecular mechanisms by which retinoids exert their inhibitory effects on breast cancer cells. The resulting knowledge will subsequently allow us to identify the optimum candidates for treatment of this disease. The retinoid design and synthesis efforts of Project Retinoid Design and Synthesis will provide essential probes for mechanism of action studies and candidates for bioevaluation. Project Molecular Mechanism of Retinoid Action will (1) investigate how RARbeta interacts with the betaRARE or is lost in breast cancer and (2) evaluate the targets for their abilities to induce or repress gene transcription. Project Retinoid-Receptor Interaction will (1) study retinoid-induced conformational changes in the RARs and RXRs as heterodimers alone or bound to retinoid response elements; (2) use an in vitro transcription system to assess modulation of the RARbeta response, and (3) characterize the receptor for the retinoid 6-[3-(1-adamantyl)]-2-naphthalenecarboxylic acid (AHPN), which induces apoptosis independently of the retinoid receptors. Project Apoptosis in Breast Cancer will (1) investigate the mechanism of action of AHPN by tracing AHPN apoptotic activity in breast cancer cell lines and isolating the AHP receptor; (2) evaluate AHPN analogs for their inhibitory activity against breast cancer cell growth; and (3) conduct breast cancer xenograft studies on the optimum retinoids/AHPN analogs. The Bioassay Core will conduct (1) retinoid receptor binding studies, (2) an angiogenesis assay, and (3) pharmacologic/toxicological/metabolic assessment to assist the Projects in selecting targets for bioevaluation or use as mechanistic probes by the Decision Network method.