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/EBPβ transcript or via proteolytic cleavage of the full-length C/EBPβ protein. Gene deletion of individual C/EBP family members has demonstrated an essential role for C/EBPβ in normal mammary development, while transgenic and overexpression studies provide evidence that the dominant-negative C/EBPβ-liver-enriched inhibitory protein isoform induces proliferation in mammary epithelial cells. Mounting evidence suggests that alterations in the ratio of the C/EBPβ-liver-enriched inhibitory protein isoform and the C/EBPβ-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.
Highlights
Breast cancer is, in part, a result of the overexpression of transcription factors that disrupt the delicate balance between cellular proliferation, terminal differentiation and programmed cell death
C/EBPδ appears to be most important for growth arrest and apoptosis, whereas C/EBPβ is necessary for growth and differentiation
The functional analysis of C/EBPβ is made more complicated by the presence of the liver-enriched inhibitory protein (LIP) and liver-enriched activating protein (LAP) isoforms, which may have opposing actions on growth and are not always expressed as a 1:1 ratio
Summary
In part, a result of the overexpression of transcription factors that disrupt the delicate balance between cellular proliferation, terminal differentiation and programmed cell death. C/EBPβ, C/EBPα and C/EBPδ are differentially and temporally expressed to coordinately control mammary growth, differ114 entiation, and programmed cell death. Transcription of the intronless C/EBPβ gene results in a single 1.4 kb mRNA that can be translated via alternative start sites into three isoforms: fulllength, 38 kDa liver-enriched activating protein (LAP)1; 35 kDa LAP2; and 20 kDa liver-enriched inhibitory protein (LIP).
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