Leissner P, Verjat T, Bachelot T, Paye M, Krause A, Puisieux A et al.. Prognostic significance of urokinase plasminogen activator and plasminogen activator inhibitor-1 mRNA expression in lymph node- and hormone receptor-positive breast cancer. BMC Cancer 6: 216

Oncology & Human Genetics Department, bioMérieux SA, Grenoble, F-38024, France.
BMC Cancer (Impact Factor: 3.36). 08/2006; 6(1):216. DOI: 10.1186/1471-2407-6-216
Source: PubMed


One of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system that comprises of, among others, the urokinase Plasminogen Activator (uPA) and its main inhibitor, the Plasminogen Activator Inhibitor-1 (PAI-1). In this study, we investigated the prognostic value of uPA and PAI-1 at the mRNA level in lymph node- and hormone receptor-positive breast cancer.
The study included a retrospective series of 87 patients with hormone-receptor positive and axillary lymph node-positive breast cancer. All patients received radiotherapy, adjuvant anthracycline-based chemotherapy and five years of tamoxifen treatment. The median patient age was 54 and the median follow-up time was 79 months. Distant relapse occurred in 30 patients and 22 patients died from breast cancer during follow-up. We investigated the prognostic value of uPA and PAI-1 at the mRNA level as measured by real-time quantitative RT-PCR.
uPA and PAI-1 gene expression was not found to be correlated with any of the established clinical and pathological factors. Metastasis-free Survival (MFS) and Breast Cancer specific Survival (BCS) were significantly shorter in patients expressing high levels of PAI-1 mRNA (p < 0.0001; p < 0.0001; respectively). In Cox multivariate analysis, the level of PAI-1 mRNA appeared to be the strongest prognostic factor for MFS (Hazard Ratio (HR) = 10.12; p = 0.0002) and for BCS (HR = 13.17; p = 0.0003). Furthermore, uPA gene expression was not significantly associated neither with MFS (p = 0.41) nor with BCS (p = 0.19). In a Cox-multivariate regression analysis, uPA expression did not demonstrate significant independent prognostic value.
These findings indicate that high PAI-1 mRNA expression represents a strong and independent unfavorable prognostic factor for the development of metastases and for breast cancer specific survival in a population of hormone receptor- and lymph node-positive breast cancer patients.


Available from: Alain Puisieux
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    • "To date, both uPA and uPAR are associated with invasiveness and metastasis of a variety of cancers, including EOC (Dass et al., 2008). In breast carcinoma, uPA/PAI-1 expression levels have provided clinically relevant information on the risk of relapse and may have relevance when choosing endocrine therapies and chemotherapy (Leissner et al., 2006); PAI-1 has been associated with shorter recurrence-free and overall survival, although its expression is rarely used as prognostic/predictive factor, as protein-based assays are difficult to routinely adopt to the limited amount of biopsy tissue that is generally available (Look et al., 2002). In contrast, in EOC PAI-1 expression in ascites could be more easily tested compared with other tumors. "
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    ABSTRACT: The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, is expressed in up to 70% of epithelial ovarian cancers (EOCs), where it correlates with poor prognosis. The majority of EOCs are diagnosed at an advanced stage, and at least 50% present malignant ascites. High levels of IL-6 have been found in the ascites of EOC patients and correlate with shorter survival. Herein, we investigated the signaling cascade led by EGFR activation in EOC and assessed whether EGFR activation could induce an EOC microenvironment characterized by pro-inflammatory molecules. In vitro analysis of EOC cell lines revealed that ligand-stimulated EGFR activated NFkB-dependent transcription and induced secretion of IL-6 and plasminogen activator inhibitor (PAI-1). IL-6/PAI-1 expression and secretion were strongly inhibited by the tyrosine kinase inhibitor AG1478 and EGFR silencing. A significant reduction of EGF-stimulated IL-6/PAI-1 secretion was also obtained with the NFkB inhibitor dehydroxymethylepoxyquinomicin. Of 23 primary EOC tumors from advanced-stage patients with malignant ascites at surgery, 12 co-expressed membrane EGFR, IL-6 and PAI-1 by immunohistochemistry; both IL-6 and PAI-1 were present in 83% of the corresponding ascites. Analysis of a publicly available gene-expression data set from 204 EOCs confirmed a significant correlation between IL-6 and PAI-1 expression, and patients with the highest IL-6 and PAI-1 co-expression showed a significantly shorter progression-free survival time (P=0.028). This suggests that EGFR/NFkB/IL-6-PAI-1 may have a significant impact on the therapy of a particular subset of EOC, and that IL-6/PAI-1 co-expression may be a novel prognostic marker.
    Oncogene 12/2011; 31(37):4139-49. DOI:10.1038/onc.2011.572 · 8.46 Impact Factor
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    • "In breast cancer, Witzel et al. [35] have reported that patients with high PAI-1 mRNA expression have a reduced 10-year disease-free survival and overall survival rate, and PAI-1 mRNA expression might reveal additional clinically relevant information compared to PAI-1 protein levels. In other studies that have analyzed PAI-1 mRNA expression in different sets of breast cancer patients, high PAI-1 mRNA levels were found to be significantly associated with shorter metastasis-free or overall survival, whereas uPA mRNA levels had no prognostic relevance [37,38]. However, in a subset of ErbB2-positive breast cancer patients, Urban et al. [29] have identified uPA mRNA as the most significant marker associated with distant metastasis-free survival, whereas PAI-1 mRNA was found to be significantly associated with distant metastasis-free survival, independent of the ErbB2 status. "
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    ABSTRACT: Members of the urokinase-type plasminogen activator (uPA) system are up-regulated in various solid malignant tumors. High antigen levels of uPA, its inhibitor PAI-1 and its receptor uPAR have recently been shown to be associated with poor prognosis in soft-tissue sarcoma (STS) patients. However, the mRNA expression of uPA system components has not yet been comprehensively investigated in STS patients. The mRNA expression level of uPA, PAI-1, uPAR and an uPAR splice variant, uPAR-del4/5, was analyzed in tumor tissue from 78 STS patients by quantitative PCR. Elevated mRNA expression levels of PAI-1 and uPAR-del4/5 were significantly associated with clinical parameters such as histological subtype (P = 0.037 and P < 0.001, respectively) and higher tumor grade (P = 0.017 and P = 0.003, respectively). In addition, high uPAR-del4/5 mRNA values were significantly related to higher tumor stage of STS patients (P = 0.031). On the other hand, mRNA expression of uPA system components was not significantly associated with patients' survival. However, in STS patients with complete tumor resection (R0), high PAI-1 and uPAR-del4/5 mRNA levels were associated with a distinctly increased risk of tumor-related death (RR = 6.55, P = 0.054 and RR = 6.00, P = 0.088, respectively). Strikingly, R0 patients with both high PAI-1 and uPAR-del4/5 mRNA expression levels showed a significant, 19-fold increased risk of tumor-related death (P = 0.044) compared to the low expression group. Our results suggest that PAI-1 and uPAR-del4/5 mRNA levels may add prognostic information in STS patients with R0 status and distinguish a subgroup of R0 patients with low PAI-1 and/or low uPAR-del4/5 values who have a better outcome compared to patients with high marker levels.
    BMC Cancer 06/2011; 11(1):273. DOI:10.1186/1471-2407-11-273 · 3.36 Impact Factor
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    • "Rome, Italy of urokinase-plasminogen activation cascade was detected in cancer tissues and correlated with a more aggressive phenotype (Borgfeldt et al. 2001; Foca et al. 2000). Urokinase is universally considered a strong and independent unfavorable prognostic factor in breast cancer (Leissner et al. 2006; Harbeck et al. 2002; Look et al. 2002; Jänicke et al. 2001; Harris et al. 2007). "
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    ABSTRACT: Increased expression of urokinase (uPA), a member of the serine protease family, is an effector of metastatic cascade and has been reported in various malignancies, including breast cancer. uPA overexpression in cancer tissues was correlated with a more aggressive phenotype and it is considered a strong and independent unfavorable prognostic factor in breast cancer. Using real-time PCR assay, we analyzed uPA expression of malignant and benign breast nodular lesions versus healthy tissues (normal breast and lymphocytes). We found that besides breast cancer nodule, normal mammary gland and lymphocytes overexpressed uPA too. Tissues obtained from women with benign lesions expressed homogeneous and lower uPA. In conclusion, although uPA overexpression is typical of cancer tissues, it could be considered as a feature of the whole organism affected by cancer. On the basis of these first results, uPA could be considered for further studies as a possible useful therapeutic target in breast cancer.
    Journal of Cancer Research and Clinical Oncology 10/2009; 136(1):157-63. DOI:10.1007/s00432-009-0694-1 · 3.08 Impact Factor
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