CCAAT/enhancer binding protein beta (C/EBPβ)-2 transforms normal mammary epithelial cells and induces epithelial to mesenchymal transition in culture

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Abstract
The transcription factor CCAAT/enhancer binding protein (C/EBP)β is critical for normal growth and differentiation of the mammary gland. The intronless C/EBPβ gene encodes a single mRNA that produces three protein isoforms, C/EBPβ-1, -2, and -3, which share a common basic-leucine zipper domain at their C-terminus, but are distinguished at their N-termini by the in-frame methionine codon used to initiate translation. Although C/EBPβ-1 and -2 are both transactivators, they likely perform distinct functions in mammary epithelial cells. C/EBPβ-1 is the only isoform detected in normal human mammary tissue. In breast cancer cell lines, C/EBPβ-1 is absent, and the C/EBPβ-2 transactivator is expressed. Moreover, our data suggest that C/EBPβ-2 is upregulated in human primary breast tumors. To assess C/EBPβ-2′s ability to participate in the transformation process, we generated recombinant retrovirus selectively encoding epitope-tagged C/EBPβ-2. Strikingly, 10 days after infecting a normal human mammary epithelial cell line (MCF10A) with C/EBPβ-2 virus, transformed subcultures were readily generated. Specifically, C/EBPβ-2-overexpressing MCF10A cells form foci, gain anchorage independence, express markers associated with having undergone an epithelial-to-mesenchymal transition, and acquire an invasive phenotype. These studies, and our previous observations, provide supportive evidence that deregulated expression of C/EBPβ-2 contributes to malignant conversion of the human breast.