CCAAT/enhancer binding proteins in normal mammary development and breast cancer

Abstract

CCAAT/enhancer binding proteins (C/EBPs) are a family of leucine zipper, transcription factors that bind to DNA as homodimers and heterodimers. They regulate cellular proliferation, differentiation and apoptosis in the mammary gland. Multiple protein isoforms, including truncated, dominant negatives, are generated by translation of the C/EBPbeta transcript or via proteolytic cleavage of the full-length C/EBPbeta protein. Gene deletion of individual C/EBP family members has demonstrated an essential role for C/EBPbeta in normal mammary development, while transgenic and overexpression studies provide evidence that the dominant-negative C/EBPbeta-liver-enriched inhibitory protein isoform induces proliferation in mammary epithelial cells. Mounting evidence suggests that alterations in the ratio of the C/EBPbeta-liver-enriched inhibitory protein isoform and the C/EBPbeta-liver-enriched activating protein isoform may play a role in the development of breast cancer. This review will consequently focus on C/EBP actions in normal mammary development and on the emerging data that supports a role in breast cancer.

Figure 1

CCAAT/enhancer binding protein beta (C/EBPβ) mRNA is translated into multiple protein isoforms. Schematic representation of C/EBPβ mRNA, its three potential translation start sites and the resultant protein isoforms. The transactivation domain, the DNA binding domain (DNA) and the leucine zipper, dimerization domain (Zipper) are indicated. It has been suggested that the upstream open reading frame (uORF) is located within a stem loop structure, and the LAP translation start sites are shown positioned on either side of the uORF. Alternative isoforms, in addition to those represented in this figure, may be present in other tissues and species. LAP, liver-enriched activating protein; LIP, liver-enriched inhibitory protein; UTR, untranslated region.