ROLE OF POLYAMINES IN ESTROGEN FUNCTION IN 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(S)及其开发新进展 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。在前一个资助期，我们发现 ER和核因子-kB与雌激素反应元件(ERE)和核因子-kB反应元件 (NRE)分别是由多胺促进的。我们的假设是 多胺是内质网和核因子-KB功能的正调节因子，多胺 类似物干扰这些转录因子的功能，诱导 细胞凋亡，并与阻断内质网或核因子-KB的化合物协同作用。在……里面 具体目标1，我们将量化结构-活性关系 通过测量DNA弯曲，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 将用于选择用于特定目的2的多胺类似物以确定 乳腺癌细胞的细胞周期阻滞和细胞凋亡的作用。初步 结果表明，Era和NF-kB信号通路在调节细胞周期蛋白Dl和 BCL-2。我们将研究多胺在雌激素激活中的作用。 Cyclin Dl和Bcl2。ERa、NF-kB的坐标识别。和 此外，还将检测由细胞周期蛋白Dl和Bcl2启动子组成的辅活化子。结果： 这些研究将被用来设计结合多胺类似物的策略 使用内质网或核因子-xB功能的抑制剂(特定目标3)。协同增长 在乳腺癌细胞中观察到的抑制和/或凋亡将得到证实 在动物模型中(特定目标4)。我们的研究将产生关于 多胺的体内外功能及新药开发进展 治疗乳腺癌。

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.