NF-kappaB-Mediated Repression of GADD153/CHOP: A Role in Breast Cancer Initiation
Abstract
The transcription factor NF-kB controls several aspects of cancer including initiation, progression, metastasis and resistance to chemotherapy. We had previously shown repression of the pro-apoptotic gene GADD153 by NF-kB in breast cancer cells. GADD153 is induced when cells are exposed to environmental stress/toxicants or deprived of nutrients. GADD153 induces apoptosis of cells with damaged DNA, which may be an essential strategy for cancer prevention. By inhibiting GADD153, NF-kB may allow accumulation of cells with damaged DNA and such cells are more prone for immortalization and transformation. In this study, we have identified NF-kB repressible element in GADD153 promoter, which binds to Snail/Gfi family of transcription repressors. Thus, NF-kB may repress gene expression by upregulating the expression of Snail/Gfi family transcription repressors. We used the immortalized mammary epithelial cell line MCF10A to determine the consequences of constitutive NFkB activation. MCF10A cells overexpressing the p65 subunit of NF-kB showed fibroblastic phenotype, which resembled the phenotype of epithelial cells that have converted to mesenchymal type (Epithelial to mesenchymal transition, EMT). EMT phenotype of p65 overexpressing cells correlated with reduced expression of epithelial specific markers E-cadherin, Desmoplakin and Keratin 18, and increased expression of mesenchymal markers Fibronectin and Vimentin compared to parental cells. MOF1OA cells overexpressing p65 showed elevated expression of transcription repressors ZEB-1 and ZEB-2. Overexpression of ZEB-1 alone was sufficient for EMT of MCF10A cells. Chronic exposure of MCF10A cells to tumor necrosis factor, a potent inducer of NF-kB, also resulted in EMT. P65 overexpression in MCF10A variants with myoepithelial phenotype, based on p63 expression pattern, resulted in loss of p63 expression. Myoepithelial cells are usually converted to myofibroblasts during invasive phase of breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2005
- Accession Number
- ADA442265
Entities
People
- Harikrishna Nakshatri
- Hui L. Chua
Organizations
- Indiana University