ROLE OF POLYAMINES IN ESTROGEN FUNCTION IN BREAST CANCER

多胺在乳腺癌雌激素功能中的作用

• 批准号: 6869573
• 负责人: THRESIA THOMAS
• 金额: $ 25.85万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-04-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869573
• 关键词: BCL2 gene /protein; analog; antineoplastics; apoptosis; breast neoplasms; cell growth regulation; chemical structure function; cyclins; estrogen receptors; estrogens; genetic regulatory element; genetically modified animals; hormone regulation /control mechanism; hormone related neoplasm /cancer; intermolecular interaction; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; nonhuman therapy evaluation; nuclear factor kappa beta; polyamines

DESCRIPTION (provided by applicant): Our goal in this proposal is to define the molecular and cellular mechanism(s) of polyamine action and to develop new breast cancer treatments. Estrogen receptor (ER) and nuclear factor kB (NF-kB) are critical transcription factors in transmitting cell growth and survival signals. During the previous funding period, we found that the interaction of ER and NF-kB with estrogen response element (ERE) and NF-KB-response element (NRE), respectively, is facilitated by polyamines. Our hypothesis is that polyamines are positive regulators of ER and NF-KB function, and polyamine analogs interfere with the function of these transcription factors, induce apoptosis, and act in synergy with compounds that block ER or NF-KB. In Specific Aim 1, we will quantify the structure-activity relationship of polyamines in ER-ERE and NF-KB-NRE interactions by measuring DNA bending, binding constants, and the conformation and stability of proteins. These data will be used to select polyamine analogs for Specific Aim 2 to determine efficacy of cell cycle arrest and apoptosis of breast cancer cells. Preliminary results indicate that ERa and NF-kB pathways merge in regulating cyclin Dl and Bcl-2. We will investigate the role of polyamines in estrogenic activation of cyclin Dl and Bcl-2. The coordinate recognition of ERalpha, NF-kB. and coactivators by cyclin Dl and Bcl-2 promoters will also be examined. Results of these studies will be used to design strategies to combine polyamine analogs with inhibitors of ER or NF-xB function (Specific Aim 3). Synergistic growth inhibition and/or apoptosis observed in breast cancer cells will be validated in animal models (Specific Aim 4). Our studies will generate information on polyamine function in vitro and in vivo and advance development new therapies for breast cancer.

描述（由申请人提供）：我们在本提案中的目标是定义 多胺作用的分子和细胞机制并开发新的 乳腺癌治疗。雌激素受体 (ER) 和核因子 kB (NF-kB) 是传递细胞生长和存活的关键转录因子 信号。在之前的资助期间，我们发现 ER 和 NF-kB 以及雌激素反应元件 (ERE) 和 NF-KB 反应元件 (NRE) 分别由多胺促进。我们的假设是 多胺是 ER 和 NF-KB 功能的正调节剂，多胺 类似物干扰这些转录因子的功能，诱导 细胞凋亡，并与阻断 ER 或 NF-KB 的化合物协同作用。在 具体目标1，我们将量化结构-活性关系 通过测量 DNA 弯曲来研究 ER-ERE 和 NF-KB-NRE 相互作用中的多胺， 结合常数以及蛋白质的构象和稳定性。这些数据 将用于选择特定目标 2 的多胺类似物以确定 乳腺癌细胞的细胞周期阻滞和凋亡的功效。初步的 结果表明 ERa 和 NF-kB 途径合并调节细胞周期蛋白 Dl 和 Bcl-2。我们将研究多胺在雌激素激活中的作用 细胞周期蛋白 D1 和 Bcl-2。 ERalpha、NF-kB的坐标识别。和 还将检查细胞周期蛋白D1和Bcl-2启动子的共激活子。结果 这些研究将用于设计结合多胺类似物的策略 与 ER 或 NF-xB 功能抑制剂一起使用（具体目标 3）。协同成长 在乳腺癌细胞中观察到的抑制和/或凋亡将得到验证 在动物模型中（具体目标 4）。我们的研究将产生以下信息 多胺在体外和体内发挥作用并促进新疗法的开发 用于乳腺癌。