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.

Fra-1, a component of the transcription factor AP-1 family, has been found to be overexpressed in carcinomas with high metastatic potential such as in triple-negative breast cancer. The effect of Fra-1 on the morphology, motility and invasive potential of breast cancer cells has been previously described. 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 the human breast cancer cell lines MCF7 (weakly invasive, estrogen receptor (ER)-positive) and MDA MB 231 (strongly invasive, ER-negative) with stable Fra-1 overexpression, we performed dynamic cell-flow adhesion assays on surfaces coated with E-selectin or with human pulmonary microvascular endothelial cells (HPMEC). Our analyses revealed increased adhesion of Fra-1 overexpressing MCF7 cells to E-selectin but also to activated endothelial cells, whereas the per se highly invasive and Fra-1-positive MDA MB 231 cell line showed enhanced cell rolling and tethering on E-selectin and endothelium-coated surfaces, but no increased firm adhesion after Fra-1 overexpression. These different behaviors correspond to an up-regulation of various adhesion-related proteins such as CD44, Integrin α5 and CEACAM6 in Fra-1 overexpressing MCF7 cells measured by microarray analysis and flow cytometry in comparison to weaker differences in the expression of adhesion molecules found in the Fra-1 overexpressing MDA MB 231 cell line. In line with these results and based on cDNA microarray data of breast cancer patients (n=175) 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. Citation Format: Leticia Oliveira-Ferrer, Melanie Kürschner, Vera Labitzky, Daniel Wicklein, Volkmar Müller, Udo Schumacher, Karin Milde-Langosch, Christine Schröder. Transcription factor Fra-1 modulates the adhesive properties of breast cancer cells contributing to a metastatic phenotype [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-17.