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，并开发新的 乳腺癌的治疗雌激素受体（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.在上一个供资期间，我们发现， ER和NF-kB与雌激素反应元件（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-κ B功能的正调节剂， 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-κ B的化合物协同作用。在 具体目标1，我们将量化的结构-活性关系 多胺在ER-ERE和NF-KB-NRE相互作用中的作用， 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 乳腺癌细胞周期阻滞和凋亡的功效。初步 结果表明ER α和NF-κ B通路在调节细胞周期蛋白D1和 Bcl-2蛋白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。ER α、NF-κ B的协同识别。和 还将检测细胞周期蛋白D1和Bcl-2启动子的共激活因子。结果 这些研究将用于设计策略，以将多胺类似物与联合收割机 与ER或NF-xB功能抑制剂联用（具体目标3）。协同生长 将验证在乳腺癌细胞中观察到的抑制和/或凋亡 在动物模型中（具体目标4）。我们的研究将产生关于 多胺在体内外的作用及新疗法的进展 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.