C/EBP(delta): A Candidate Tumor Suppressor Gene in Breast Cancer

摘要

Inactivation of tumor suppressor genes, through a variety of mechanisms, is a key pathological step in breast cancer development and progression. The overall goal of this research is to investigate the regulation, expression and clinical relevance of CCAAT/Enhancer binding protein 5 (C/EBP5, CEBPD) as a candidate tumor suppressor gene in breast cancer. Our hypothesis is that C/EBP5 is a key regulator of mammary epithelial cell growth arrest and that loss in C/EBP5 function is part of the cascade of molecular events that facilitate the progression to metastatic breast cancer. In previous reports we have shown that C/EBP8 expression is associated with growth arrest in mouse mammary epithelial cells. The data presented in this research report demonstrate the association between STAT3 activation, C/EBP8 gene expression and growth arrest in human mammary epithelial cells. 'Loss of function' alterations in the Stat3/C/EBP5 are common in human breast cancer cell lines. In addition, we show that the C/EBP5 gene exhibits relatively few nucleotide sequence alterations in clinical breast cancer. The C/EBP6 gene promoter, however, exhibits extensive CpG methylation and gene silencing in the SUM-52PE cell line and variable CpG methylation that is associated with reduced C/EBP8 gene expression in primary human breast cancer samples. Hence, alterations in the Stat3/C/EBP5 growth inhibitory pathway may play an important role in the etiology or progression of breast cancer.