Genetic aberrations affecting either interferon gamma (IFNgamma) or BRCA1 signaling have been directly implicated in human breast cancer. We have recently identified BRCA1 as coactivator of STAT1 transcription factor, but the complexity of STAT1 regulated gene expression elucidated to date suggests that other components remain to be defined. More recently, it has been shown that human breast cancer cells show the distinct patterns of expression of IFNgamma target genes from normal epithelial cells, implying the correlation of IFNgamma signaling and breast cancer development. Through the analysis of IFN-induced genes, we have identified IFI-16 as a target of IFN/BRCA1 system since BRCA1 binds to and enhances IFI-16-dependent transcriptional regulation. Significantly, we have found that IFI-16 also physically interacts with p53 resulting to synergistic activation, which was further enhanced by BRCA1. We have further discovered that several human breast cancer cell lines examined express quite low level of IFI-16 compared to normal mammary epithelial cells.
Aims of this grant application include exploration of novel functions uncovered by us for a prototype STAT1 transcription factor and BRCA1 breast cancer suppressor protein, structure/function analysis of these proteins. Our goals would be to use this knowledge to investigate novel mechanisms of IFNgamma/STAT1/BRCA1 system in tumor suppression. A second major aim would be the functional analysis of IFI16/BRCA1 and IFI-16/p53 complex. The functions of newly identified IFI-16 in inducing or suppressive aspects of the transformed phenotype in vitro would be explored.
The final aim would be to characterize novel mechanisms of BRCA1 regulation of cell proliferation.
These Aims are supported by our findings of IFNgamma activation of p21WAF1, not other known IFNgamma target promoters, requires wild type BRCA1. Furthermore, we discovered that Fas antigen is a major target of IFI-16, and that expression of IFI-16 causes apoptosis. Taken together with the frequent mutations of BRCA1 locus in familial breast cancer patients, the failure of IFNgamma regulation of cell proliferation due to the loss of BRCA1 could provide insights into the molecular basis for the escape from growth suppression by IFNgamma in tumor evolution as well as the potential for therapeutic intervention with STAT1/BRCA1 signaling. In addition, our previous discovery of p53 activation by BRCA1 strongly supports an idea that there is a functional interaction between the BRCA1/STAT1/IFI-16 signaling cascade and the BRCA1/p53/IFI-16 network, and that the perturbation of this cross talk is closely associated with human cancer development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090631-03
Application #
6769419
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mietz, Judy
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2004-09-03
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$339,424
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Fernández-Jaén, Alberto; Álvarez, Sara; So, Eui Young et al. (2016) Mutations in BRAT1 cause autosomal recessive progressive encephalopathy: Report of a Spanish patient. Eur J Paediatr Neurol 20:421-5
Sancho, Sara Cuesta; Olson, Susan Losee; Young So, Eui et al. (2016) Fibersol-2 induces apoptosis of Apc-deficient colorectal Cancer (SW480) cells and decreases polyp formation in Apc MIN mice. Cancer Biol Ther 17:657-63
Sancho, Sara Cuesta; Ouchi, Toru (2015) Cell Differentiation and Checkpoint. Int J Cancer Res Mol Mech 1:
So, Eui Young; Ouchi, Mutsuko; Cuesta-Sancho, Sara et al. (2015) Tumor suppression by resistant maltodextrin, Fibersol-2. Cancer Biol Ther 16:460-5
So, E Y; Ouchi, T (2014) Translational initiation regulated by ATM in dendritic cells development. Cell Death Dis 5:e1418
So, Eui Young; Ouchi, Toru (2014) BRAT1 deficiency causes increased glucose metabolism and mitochondrial malfunction. BMC Cancer 14:548
So, Eui Young; Ouchi, Toru (2014) Decreased DNA repair activity in bone marrow due to low expression of DNA damage repair proteins. Cancer Biol Ther 15:906-10
Shionome, Yoshimi; Lin, Wen-Hsing; Shiao, Hui-Yi et al. (2013) A novel aurora-A inhibitor, BPR1K0609S1, sensitizes colorectal tumor cells to 5-fluorofracil (5-FU) treatment. Int J Biol Sci 9:403-11
So, Eui Young; Kozicki, Martin; Ouchi, Toru (2013) Roles of DNA Damage Response Proteins in Mitogen-Induced Thp-1 Differentiation into Macrophage. J Cancer Biol Res 1:
So, Eui Young; Ouchi, Toru (2013) The Potential Role of BRCA1-Associated ATM Activator-1 (BRAT1) in Regulation of mTOR. J Cancer Biol Res 1:

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