Expression profiling of 5 novel breast cancer cell lines

The Fra-1 transcription factor promotes tumor cell growth, invasion and metastasis. While characterizing five breast cancer cell lines derived from primary human breast tumors, we identified BRC-31 as a novel basal-like cell model that expresses elevated Fra-1 levels. BRC-31 cells display elevated FAK, SRC and ERK2 phosphorylation relative to luminal breast cancer models. Inhibition of this signaling axis, through the use of pharmacological inhibitors, reduces the phosphorylation and stabilization of Fra-1. Elevated integrin V3 expression in these cells suggested that integrin receptors might activate this FAK-SRC-ERK2 signaling axis to enhance Fra-1 phosphorylation. These cells also express high levels of uPAR, a GPI-anchored receptor that has been shown to enhance integrin-mediated signaling initiated by Vitronectin engagement. Transient knockdown of uPAR in BRC31 cells grown on Vitronectin reduces Fra-1 phosphorylation and stabilization and uPAR and Fra-1 are required for Vitronectin-induced cell invasion. In clinical samples, a molecular component signature consisting of Vitronectin-uPAR-uPA-Fra-1 predicts poor overall survival in patients with breast cancer and correlates with a Fra-1 transcriptional signature. Taken together, we have identified a novel-signaling axis that leads to phosphorylation and stabilization of Fra-1, a transcription factor that is emerging as an important modulator of breast cancer progression and metastasis.

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Annis MG, Ouellet V, Rennhack JP, L'Esperance S, Rancourt C, Mes-Masson AM, Andrechek ER, Siegel PM