C/EBPbeta-2 confers EGF-independent growth and disrupts the normal acinar architecture of human mammary epithelial cells.
BACKGROUND
The transcription factor, C/EBPbeta, is a key regulator of growth and differentiation in the mammary gland. There are three different protein isoforms of C/EBPbeta. C/EBPbeta-1 and -2 are transactivators, and differ by only 23 N-terminal amino acids present in beta-1 only. C/EBPbeta-3 (LIP) lacks the transactivation domain and represses transcription. Elevated C/EBPbeta-2 expression causes MCF10A normal human mammary epithelial cells to become transformed, undergo an epithelial to mesenchymal transition (EMT), and acquire an invasive phenotype. C/EBPbeta is a downstream transcriptional target of Ras signaling pathways and is required for Ras transformation of some cell types. Ras signaling pathways are activated in mammary epithelial cells by the ErbB receptor tyrosine kinase family. Therefore, we considered whether elevated C/EBPbeta-2 expression would resemble ErbB RTK activation in MCF10A cells.


RESULTS
We show that elevated C/EBPbeta-2 expression confers EGF-independent growth in MCF10A mammary epithelial cells. However, MCF10A cells expressing C/EBPbeta-3 are not EGF-independent, and high C/EBPbeta-3 or LIP expression is incompatible with growth. C/EBPbeta-2 overexpression disrupts the normal acinar architecture of MCF10A cells in basement membrane cultures and induces complex multiacinar structures with filled lumen, similar to the consequences of aberrant ErbB2 activation.


CONCLUSIONS
Given the ability of C/EBPbeta-2 to confer EGF-independent growth to mammary epithelial cells as well as its capability for disrupting normal epithelial architecture and causing EMT, it is worth considering whether inhibitors which target ErbB family signaling pathways could be less effective in mammary epithelial cells with elevated nuclear C/EBPbeta-2 expression.
Bundy
Linda
L
Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. linda.bundy@vanderbilt.edu
Wells
Sam
S
Sealy
Linda
L
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction
D022782:CCAAT-Enhancer-Binding Protein-beta