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01.12.2018 | Research Article | Ausgabe 1/2018 Open Access

Breast Cancer Research 1/2018

Integrin-uPAR signaling leads to FRA-1 phosphorylation and enhanced breast cancer invasion

Zeitschrift:
Breast Cancer Research > Ausgabe 1/2018
Autoren:
Matthew G. Annis, Veronique Ouellet, Jonathan P. Rennhack, Sylvain L’Esperance, Claudine Rancourt, Anne-Marie Mes-Masson, Eran R. Andrechek, Peter M. Siegel
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13058-018-0936-8) contains supplementary material, which is available to authorized users.

Abstract

Background

The 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.

Methods

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. 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.

Results

BRC-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.

Conclusions

We 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.
Zusatzmaterial
Additional file 1: Oligonucleotides utilized in this manuscript. (XLSX 47 kb)
13058_2018_936_MOESM1_ESM.xlsx
Additional file 2: Document 1: Supplemental Figure legends and Methods. (DOCX 86 kb)
13058_2018_936_MOESM2_ESM.docx
Additional file 3: Figure S1. Gene Expression of mapk1, mapk3 and fosl1 in human Breast Cancer Cell lines. (PPTX 1395 kb)
13058_2018_936_MOESM3_ESM.pptx
Additional file 4: Figure S2. EGFR inhibition is not sufficient to decrease phosphorylation on FRA-1. (PPTX 4508 kb)
13058_2018_936_MOESM4_ESM.pptx
Additional file 5: Figure S3. FRA-1 phosphorylation occurs prior to cell spreading. (PPTX 4024 kb)
13058_2018_936_MOESM5_ESM.pptx
Additional file 6: Figure S4. Gene Expression of plaur in human Breast Cancer Cell lines. (PPTX 1129 kb)
13058_2018_936_MOESM6_ESM.pptx
Additional file 7: Figure S5. Knockdown of plaur or fosl1 does not affect cell proliferation. (PPTX 515 kb)
13058_2018_936_MOESM7_ESM.pptx
Additional file 8: Figure S6. Basal-like breast cancer cell lines and patient-derived xenografts (PDXs) that possess elevated FRA-1 phosphorylation display high uPAR and uPA expression. (PPTX 1129 kb)
13058_2018_936_MOESM8_ESM.pptx
Literatur
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