ROLE FOR NF-KB IN CARCINOGEN INDUCED BREAST CANCER

描述 核因子-kappaB是一种可诱导的转录因子 它调节一组与免疫和炎症有关的基因 回应。最近，我们和其他人证明了核因子-kappaB的激活 可阻断肿瘤坏死因子、辐射或癌症诱导的细胞凋亡 化疗。此外，我们已经证明，RAS激活了 核因子-kappaB通过应激激活蛋白的转录功能 而核因子-kappaB的抗细胞凋亡作用是 癌基因RAS和bcr-Abl诱导的细胞转化所必需的。 我们的数据和其他人的数据表明，核因子-kappaB在 人类乳腺癌。此外，7，12-二甲基苯-(A)-菲(DMBA) 是乳腺肿瘤发生的化学诱导剂，是一种细胞凋亡 刺激可能通过诱导DNA损伤来实现。有趣的是， 化学保护剂白藜芦醇阻断DNA诱导 小鼠乳腺肿瘤的发生。我们的初步数据显示 白藜芦醇可阻断核因子-kappaB的诱导 细胞因子，肿瘤坏死因子，以及细菌内毒素， 脂多糖(LPS)。研究方案的目标是：(1) 确定核因子-kappaB是否参与致癌物诱发的乳腺 肿瘤的发生可能是通过核因子-kappaB的抗凋亡功能， (2)阐明DMBA是否激活核因子-kappaB；(3)测定 白藜芦醇作为化学预防药物的抑制作用 致癌物诱导的kappaB在致癌物诱导的乳腺肿瘤发生中的作用 确定核因子-kappaB是否参与发病机制 并将确定核因子-kappaB是否是一个特定的靶点 用于化学预防药物。

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.