NF-kappaB-Mediated Repression of GADD153/CHOP: A Role in Breast Cancer Initiation
Abstract
Cells under endoplasmic reticulum stress show increased expression of GADD153, a pro-apoptotic C/EBP family transcription factor. Cellular stress also induces the activity of the transcription factor NF-kB, which promotes cell survival. We showed inhibition of GADD153 mRNA expression by the p65 transactivating subunit of NF-kB and proposed that of cells expressing constitutively active NF-kB may be predisposed to transformation following cellular stress due to p65-mediated inhibition of GADD153 expression. We generated immortalized mammary epithelial cells MCF-10A overexpressing p65. p65 overexpressing cells showed hallmarks of epithelial to mesenchymal transition (EMT) including reduced expression of E-cadherin and Occludin and increased expression of Vimentin and stromelysin-1. The expression pattern of c/EBPbeta was altered in p65 overexpressing cells compared to parental cells. Parental MCF10A cells cultured in matrigel organized into polarized lobular acinar structures, whereas MCF10A/p65 cells formed disorganized structures, similar to ErbB2-transfected MCF10A cells. Interestingly, the expression levels of the transcription repressors ZEB-1 and ZEB-2 but not Snail, all of which are involved induction of EMT, were elevated in MCF10A/p65 cells. P65 reduced the expression of deltaNp63, a marker for myoepithelial cells. We have also identified the transcription repressor oncoprotein Gfi-1 as the transcriptional target of NF-kB and Gfi-1 reduced GADD153 expression. These results suggest that NF-kB promotes breast cancer initiation through EMT, inducing the expression of oncoprotein such as Gfi-1.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2004
- Accession Number
- ADA428234
Entities
People
- Harikrishna Nakshatri
- Hui L. Chua
Organizations
- Indiana University