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.
| Holmes-McNary, M (2001) Impact factors on development of cirrhosis and subsequent hepatocellular carcinoma. Compend Contin Educ Dent 22:19-33 |
| Holmes-McNary, M Q; Baldwin Jr, A S; Zeisel, S H (2001) Opposing regulation of choline deficiency-induced apoptosis by p53 and nuclear factor kappaB. J Biol Chem 276:41197-204 |
| Holmes-McNary, M; Baldwin Jr, A S (2000) Chemopreventive properties of trans-resveratrol are associated with inhibition of activation of the IkappaB kinase. Cancer Res 60:3477-83 |
