ROLE FOR NF-KB IN CARCINOGEN INDUCED BREAST CANCER

NF-KB 在致癌物诱发的乳腺癌中的作用

• 批准号: 6173661
• 负责人: Minnie Q Holmes-McNary
• 金额: $ 4.26万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-25 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6173661
• 关键词: animal genetic material tag; apoptosis; benzanthracenes; breast neoplasms; cell proliferation; chemical carcinogenesis; chemoprevention; enzyme activity; enzyme inhibitors; genetically modified animals; laboratory mouse; neoplasm /cancer genetics; nuclear factor kappa beta; nutrition related tag; protein kinase; protein structure function

DESCRIPTION Nuclear factor kappa B (NF-kappaB) is an inducible transcription factor that regulates a group of genes involved in immune and inflammatory responses. Recently, we and other demonstrated that NF-kappaB activation can block apoptosis induced by tumor necrosis factor, radiation or cancer chemotherapies. Additionally, we have shown that Ras activated the transcriptional function of NF-kappaB through a stress-activated protein kinase (SAPK) pathway and that the anti-apoptotic function of NF-kappaB is required for cellular transformation induced by oncogenic Ras and Bcr-Abl. Our data and data from others indicated that NF-kappaB is activated in human breast cancer. Furthermore, 7,12-dimethylbenz-(a)-anthracene (DMBA) is a chemical-inducer of mammary tumorigenesis and is an apoptotic stimulus possibly through the induction of DNA-damage. Interestingly, the chemopreventative agent, resveratrol blocked the induction of DNA-induced mouse mammary tumorigenesis. Our preliminary data indicate that resveratrol can block the induction of NF-kappaB induced by the potent cytokine, TNF-alpha, as well as the bacterial endotoxin, lipopolysaccharide (LPS). The goals of the research proposal are to: (1) determine whether NF-kappaB is involved in carcinogen-induced mammary tumorigenesis possibly through the anti-apoptotic function of NF-kappaB, (2) elucidate whether DMBA activates NF-kappaB, and (3) determine the effectiveness of resveratrol as a chemopreventative agent on inhibiting carcinogen-induced kappaB in carcinogen-induced breast tumorigenesis, will establish whether NF-kappaB is specifically involved in the pathogenesis of breast cancer and will determine whether NF-kappaB is a specific target for chemopreventative agents.

描述 核因子 kappa B (NF-kappaB) 是一种诱导型转录因子 调节一组涉及免疫和炎症的基因 回应。最近，我们和其他人证明了 NF-kappaB 激活 可以阻断肿瘤坏死因子、辐射或癌症诱导的细胞凋亡 化疗。此外，我们还表明 Ras 激活了 NF-kappaB 通过应激激活蛋白的转录功能 激酶 (SAPK) 通路以及 NF-kappaB 的抗凋亡功能是 致癌 Ras 和 Bcr-Abl 诱导的细胞转化所需的。 我们的数据和其他人的数据表明 NF-kappaB 在 人类乳腺癌。此外，7,12-二甲基苯并-(a)-蒽 (DMBA) 是乳腺肿瘤发生的化学诱导剂，并且是细胞凋亡的 刺激可能是通过诱导 DNA 损伤来实现的。有趣的是， 化学预防剂，白藜芦醇阻断DNA诱导的诱导 小鼠乳腺肿瘤发生。我们的初步数据表明 白藜芦醇可以阻断强效物质诱导的 NF-κB 诱导 细胞因子、TNF-α以及细菌内毒素， 脂多糖（LPS）。研究计划的目标是：（1） 确定 NF-kappaB 是否参与致癌物诱导的乳腺 肿瘤发生可能通过 NF-κB 的抗凋亡功能， (2) 阐明 DMBA 是否激活 NF-kappaB，以及 (3) 确定 白藜芦醇作为化学预防剂对抑制的有效性 致癌物诱导的 kappaB 在致癌物诱导的乳腺肿瘤发生中，将 确定 NF-κB 是否特异性参与发病机制 乳腺癌，并将确定 NF-kappaB 是否是特定靶点 用于化学预防剂。