Analysis of a Causal Role for ESX in Human Breast Cancer
Abstract
A growing body of evidence supports an oncogenic role for the ETS transcription factor ESX in breast cancer. ESX over-expression is detected in human breast cancer tissues and we have previously reported that the ESX- negative and nontransformed human breast cell line, MCF-12A, is transformed by stable ESX expression. In our current snidies, we identify a unique 50-amino acid ESX domain, the SAR domain, that is sufficient to transform MCF-12A cells and whose transforming function is mediated by a novel cytoplasmic mechanism. Indeed, deletion of domains required for transcription factor function do not abrogate ESX-mediated MCF-12A cell transformation, whereas fusion of the SV4O large T antigen nuclear localization signal to either full-length ESX or to the ESX SAR domain alone blocked their transforming functions. Further, we find that ESX expression in transiently transfected cells is initially nuclear and mediates apoptosis. Together, our studies demonstrate two separate functions for the ESX transcription factor, apoptosis and transformation. Further, these two functions have distinct mechanisms: ESX-mediated apoptosis depends on nuclear ESX protein localization and appears to result from ESX function in transcription regulation. In contrast, ESX function in mammary epithelial cell transformation is mediated by the cytoplasmic function of its novel SAR domain.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2003
- Accession Number
- ADA420155
Entities
People
- Jason D. Prescott
Organizations
- University of Colorado Health