Two cell lines originating from a common ancestral
tumor, CSML0 and CSML100, were used as a model to study
AP-1 transcription factors at different steps of
tumor progression. CSML0 cells have an epithelial morphology; they express epithelial but not mesenchymal markers and are invasive neither in vitro nor in vivo. CSML100 possesses all characteristics of a highly progressive
carcinoma. These cells do not form tight contacts, are highly invasive in vitro, and are metastatic in vivo.
AP-1 activity was considerably higher in CSML100 cells than in CSML0 cells. There was a common predominant Jun component, namely, JunD, detected in both cell lines. We found that the enhanced level of
AP-1 in CSML100 cells was due to high expression of Fra-1 and Fra-2
proteins, which were undetectable in CSML0 nuclear extracts. Analysis of the transcription of different
AP-1 members in various cell lines derived from
tumors of epithelial origin revealed a correlation of fra-1 expression with mesenchymal characteristics of
carcinoma cells. Moreover, we show here for the first time that the expression of exogenous Fra-1 in epithelioid cells results in morphological changes that resemble fibroblastoid conversion. Cells acquire an elongated shape and become more motile and invasive in vitro. Morphological alterations were accompanied by transcriptional activation of certain genes whose expression is often induced at late stages of
tumor progression. These data suggest a critical role of the
Fra-1 protein in the development of epithelial
tumors.