Abstract
BackgroundThe Fos-related antigen 1 (FRA-1) transcription factor promotes tumor cell growth, invasion and metastasis. Phosphorylation of FRA-1 increases protein stability and function. We identify a novel signaling axis that leads to increased phosphorylation of FRA-1, increased extracellular matrix (ECM)-induced breast cancer cell invasion and is prognostic of poor outcome in patients with breast cancer.MethodsWhile 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. We interrogated the functional contribution of FRA-1 and an upstream signaling axis in breast cancer cell invasion. We extended this analysis to determine the prognostic significance of this signaling axis in samples derived from patients with breast cancer.ResultsBRC-31 cells display elevated focal adhesion kinase (FAK), SRC and extracellular signal-regulated (ERK2) phosphorylation relative to luminal breast cancer models. Inhibition of this signaling axis, with pharmacological inhibitors, reduces the phosphorylation and stabilization of FRA-1. Elevated integrin αVβ3 and uPAR expression in these cells suggested that integrin receptors might activate this FAK-SRC-ERK2 signaling. Transient knockdown of urokinase/plasminogen activator urokinase receptor (uPAR) in basal-like breast cancer 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 an FRA-1 transcriptional signature.ConclusionsWe have identified a novel signaling axis that leads to phosphorylation and enhanced activity of FRA-1, a transcription factor that is emerging as an important modulator of breast cancer progression and metastasis.
Highlights
The Fos-related antigen 1 (FRA-1) transcription factor promotes tumor cell growth, invasion and metastasis
We examined the expression of genes within the Affymetrix dataset that are characteristic of each intrinsic subtype including the estrogen receptor and progesterone receptor, the ErbB2 receptor tyrosine kinase (human epidermal growth factor receptor 2 (HER2)+ subtype) or the epidermal growth factor receptor
To further validate the basal nature of BRC-31 cells, we examined the expression of epithelial (E-cadherin, cytokeratin-8) and mesenchymal (N-cadherin, fibronectin and vimentin) markers
Summary
The Fos-related antigen 1 (FRA-1) transcription factor promotes tumor cell growth, invasion and metastasis. The transcription factor Fos-related antigen 1 (FRA-1) influences tumor heterogeneity [1] and is an important driver of cancer cell stemness and resistance in breast cancer [2]. One study failed to detect an association between FRA-1 protein expression and overall survival [16], while others identified positive correlation between FRA-1 gene expression and shorter time to distant metastasis [2, 17, 18]. A curated FRA-1 transcriptional signature, when applied to numerous gene expression data sets, showed positive correlation with shorter time to distant metastasis or relapse across breast cancer subtypes [9, 10]. High FRA-1 expression was shown to be correlated with shorter overall survival and higher rates of lung metastases in patients with estrogen receptor (ER)positive disease but not ER-negative cancers [19]
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