Prognostic impact of transcription factor Fra-1 in ER-positive breast cancer: contribution to a metastatic phenotype through modulation of tumor cell adhesive properties

The transcription factor Fos-related antigen-1 (Fra-1) has been described to affect the morphology, motility and invasive potential of breast cancer cells. Since tumor cell adhesion plays an essential role in the metastatic process, especially for extravasation from blood vessels, we investigated the influence of Fra-1 on breast cancer cell interactions with the endothelium. Using Fra-1-overexpressing MCF7 [weakly invasive, estrogen receptor (ER)-positive] and MDA MB231 (strongly invasive, ER-negative) cells, we performed dynamic cell flow adhesion assays on surfaces coated with E-selectin or with human pulmonary microvascular endothelial cells. We found a significant increased adhesion of Fra-1-overexpressing MCF7 cells to E-selectin but also to activate endothelial cells, whereas the MDA MB231 cell line showed moderate enhanced cell rolling and tethering on both coated surfaces. These different adhesion behaviors corresponded to an up-regulation of various adhesion-related proteins such as CD44 and integrin alpha 5 in Fra-1-overexpressing MCF7 cells measured by microarray analysis and flow cytometry in comparison with no deregulation of key adhesion molecules observed in Fra-1-overexpressing MDA MB231 cells. In line with these results and based on cDNA microarray data of breast cancer patients (n = 197), high Fra-1 expression significantly correlates with shorter overall survival and higher rate of lung metastasis in ER-positive breast cancer patients (n = 130), but has no impact on the prognosis of patients with ER-negative tumors. Thus, in addition to its pro-invasive and pro-migratory effect, Fra-1 might influence the metastatic potential of breast cancer cells by changing the expression of adhesion molecules, resulting in increased adherence to endothelial cells under flow conditions.