Abstract
BackgroundThe transcription factor, CCAAT enhancer binding protein-β (C/EBPβ), is expressed as several distinct protein isoforms (LAP1, LAP2 and LIP) that have opposing actions in cellular proliferation and differentiation. Increases in the ratio of LIP/LAP are associated with aggressive, metastatic breast cancer; however, little is known regarding the molecular mechanisms that regulate LIP expression or the biological actions of an increase in the LIP/LAP ratio. Metastasis is highly dependent upon the suppression of anoikis and the role of C/EBPβ and LIP in this anchorage-independent, survival process is currently not known in mammary epithelial cells. IGF-1R signaling is important for the survival of breast cancer cells and crosstalk between IGF-1R and EGFR signaling pathways have been implicated in the development of more aggressive disease. We therefore evaluated in mammary epithelial cells whether IGF-1R signaling regulates the LIP/LAP ratio, analyzed the potential interplay between EGFR and IGF-1R signaling and addressed the biological significance of increased LIP expression in cellular survival and suppression of anoikis.ResultsOur data provide the first evidence that IGF-1R signaling regulates LIP expression in an EGFR independent manner to increase the LIP/LAP ratio in mammary epithelial cells. Although crosstalk between IGF-1R signaling and EGFR signaling is detectable in MCF10A cells, this crosstalk is not required for the IGF-1 mediated regulation of LIP expression. Rather, the critical regulator of IGF-1 induced LIP expression appears to be EGFR-independent, Akt activity. Our data also demonstrate that increases in LIP expression promote cell survival via suppression of anoikis. Likewise, knockdown of total C/EBPβ leads to increased cell death and suggest that C/EBPβ expression is important for survival and resistance to anoikis. IGF-1 treatment can partially rescue vector control cells from anoikis; however, cells with reduced C/EBPβ expression do not survive anoikis.ConclusionsTaken together, our data demonstrate that IGF-1R signaling regulates LIP expression in an EGFR independent manner to increase the LIP/LAP ratio in mammary epithelial cells. C/EBPβ expression and elevations in LIP play an important role in regulating cellular survival via suppression of anoikis, in an IGF-1R mediated context or in a manner independent of IGF-1R signaling.
Highlights
The transcription factor, CCAAT enhancer binding protein-b (C/EBPb), is expressed as several distinct protein isoforms (LAP1, LAP2 and LIP) that have opposing actions in cellular proliferation and differentiation
Crosstalk between IGF1R signaling and epidermal growth factor receptor (EGFR) signaling is detectable in MCF10A cells, this crosstalk is not required for the IGF-1 mediated regulation of LIP expression
insulin-like growth factor-1 receptor (IGF-1R) increases the ratio of LIP/LAP expression To determine whether IGF-1 regulates C/EBPb-LIP expression in mammary epithelial cells, MCF10A cells were serum starved for 24 hours and stimulated with IGF-1 (2.6 nM, 20 ng/ml) for 4 or 16 hours prior to harvesting
Summary
The transcription factor, CCAAT enhancer binding protein-b (C/EBPb), is expressed as several distinct protein isoforms (LAP1, LAP2 and LIP) that have opposing actions in cellular proliferation and differentiation. Metastasis is highly dependent upon the suppression of anoikis and the role of C/EBPb and LIP in this anchorage-independent, survival process is currently not known in mammary epithelial cells. We evaluated in mammary epithelial cells whether IGF-1R signaling regulates the LIP/LAP ratio, analyzed the potential interplay between EGFR and IGF1R signaling and addressed the biological significance of increased LIP expression in cellular survival and suppression of anoikis. The LIP and LAP isoforms may have potentially opposing actions in cellular proliferation and differentiation and increases in the LIP/LAP ratio are known to be associated with tumorigenesis and metastasis. The C/EBPb isoforms thereby play an important role in high grade, metastatic breast cancer and the LIP/LAP ratio is a critical determinant in the aggressiveness of the disease
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