Poster Sessions

CANCER-3

Tapasree Roy Sarkar

T. Roy Sarkar, S. Pawar, E. Sterneck

The Src Tyrosine Kinase Represses Tumor Suppressor CEBPD Protein Expression in Breast Cancer Cells via Regulation of SIAH Ubiquitin E3 Ligases

The transcription factor CCAAT/enhancer-binding protein delta (CEBPD, C/EBPd) is a potential tumor suppressor, which inhibits the growth of tumor cell lines in vitro. C/EBPd gene expression is downregulated with malignant progression of breast tumors. We were seeking to understand how C/EBPd expression is repressed in tumors. Knowledge of this mechanism may allow pharmacological activation of C/EBPd and consequently inhibition of tumor cell growth. The cytoplasmic Src tyrosine kinase is overexpressed and/or mutated in many tumors. Inhibition of endogenous Src kinase with pharmacological inhibitors induced C/EBPd protein expression in MDA-MB-468 breast cancer cells. Conversely, overexpression of oncogenic Src inhibited expression of C/EBPd in MCF10A human breast epithelial cells. Regulation of C/EBPd expression was at the level of protein stability mediated by Seven in Absentia Homologue (SIAH) proteins (E3 Ubiquitin Ligase family protein). In contrast to Src kinase, EGF signaling induced C/EBPd expression in both cell lines. Current experiments address the potential role of C/EBPd in inhibition of cell transformation and migration in vitro and in vivo, and the molecular mechanism by which kinases regulate C/EBPd protein expression. These data will help unravel the complex interplay of different kinase signaling pathways in tumorigenesis. (191 words)