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）是诱导的转录因子 调节一组参与免疫和炎症的基因 回答。最近，我们和其他证明了NF-kappab激活 可以阻止肿瘤坏死因子，辐射或癌症引起的凋亡 化学疗法。此外，我们已经表明RAS激活了 NF-kappab通过应力激活蛋白的转录功能 激酶（SAPK）途径，NF-kappab的抗凋亡功能为 由致癌Ras和BCR-ABL诱导的细胞转化所必需的。 我们的数据和其他数据表明NF-kappab已激活 人类乳腺癌。此外，7,12-二甲基苯子 - （A） - 蒽（DMBA） 是乳腺肿瘤发生的化学诱导剂，是凋亡的 刺激可能通过诱导DNA破坏。有趣的是， 化学预防剂，白藜芦醇阻止了DNA诱导的诱导 小鼠乳腺肿瘤发生。我们的初步数据表明 白藜芦醇可以阻止有效诱导的NF-kappab的诱导 细胞因子，TNF-α以及细菌内毒素， 脂多糖（LPS）。研究建议的目标是：（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-kappab的抗凋亡功能， （2）阐明DMBA是否激活NF-kappab，（3）确定 白藜芦醇作为化学预防剂的有效性在抑制 致癌物诱导的致癌物诱导的乳腺癌的乳腺癌的乳腺肿瘤发生的Kappab将会 确定NF-kappab是否特别参与发病机理 乳腺癌，并将确定NF-kappab是否是特定目标 用于化学预防剂。