ROLE FOR NF-KB IN CARCINOGEN INDUCED BREAST CANCER

描述 核因子κ B（NF-κ B）是一种可诱导的转录因子 它调节一组与免疫和炎症相关的基因， 应答最近，我们和其他研究人员证明，NF-κ B激活 可阻断肿瘤坏死因子、放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 NF-κ B通过应激激活蛋白的转录功能 激酶（SAPK）途径，NF-κ B的抗凋亡功能是 所需的致癌Ras和Bcr-Abl诱导的细胞转化。 我们的数据和其他人的数据表明，NF-κ B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， 刺激可能通过诱导DNA损伤。有趣的是 化学预防剂白藜芦醇阻断了DNA诱导的 小鼠乳腺肿瘤发生。我们的初步数据显示， 白藜芦醇可以阻断由强效抗肿瘤药物诱导的NF-κ B的诱导， 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-κ B是否参与致癌物诱导的乳腺癌 肿瘤发生可能通过NF-κ B的抗凋亡功能， (2)阐明DMBA是否激活NF-κ B，和（3）确定 白藜芦醇作为一种化学预防剂抑制 致癌物诱导的kappaB在致癌物诱导的乳腺肿瘤发生中， 确定NF-κ B是否特异性参与发病机制 并将确定NF-kappaB是否是一个特异性靶点 用于化学预防剂。

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.