Deregulation of the interferon-gamma (IFN-GAMMA) or BRCA1 signaling has been directly implicated in human breast cancer. It has been recently identified that BRCA1 is the coactivator of STAT1 transcription factor. More recently, it has been shown that human breast cancer cells show distinct patterns of expression of IFN-GAMMA target genes from normal epithelial cells, implying the correlation of IFN-GAMMA signaling and breast cancer development. Thus, identification of the critical effectors of STAT1-mediating specific genomic promoter activation as well as BRCA1 functions requires further investigation.
The aim of this research project is to explore the novel function of IFN/STAT1/BRCA1 signaling. Components of the proteins binding to the STAT1 transactivation domain will be isolated by immunoaffinity purification. Analysis of the genomic promoter after IFN-GAMMA stimulation will be conducted and mass spectrometry techniques will be used to analyze the structure/function relationship of these proteins. The knowledge gained from this project will be used to further investigate the novel mechanism of IFN-GAMMA /STAT1/BRCA1 system in tumor suppression. Taken together with the frequent mutation of the BRCA1 locus in familial breast cancer patients, understanding the mechanism of IFN-GAMMA signaling could provide insights into the molecular basis of escape from growth suppression by IFN-GAMMA in tumor development and the potential for therapeutic intervention with STAT1/BRCA1 signaling.
|Aglipay, Jason A; Martin, Sarah A; Tawara, Hideyuki et al. (2006) ATM activation by ionizing radiation requires BRCA1-associated BAAT1. J Biol Chem 281:9710-8|