Clinical Utility of Urokinase-Type Plasminogen Activator and Plasminogen Activator Inhibitor—1 Determination in Primary Breast Cancer Tissue for Individualized Therapy Concepts

Harbeck, Nadia; Kates, Ronald; Kiechle, Marion; Zemzoum, Iris; Jänicke, F.; Thomssen, Christoph

doi:10.3816/cbc.2002.n.023

Cited by 66 publications

(40 citation statements)

References 30 publications

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“…Gene ablation and reconstitution data show that PAI1 can promote cancer progression (11)(12)(13)(14), and correlative data consistently indicate that its elevated expression in breast tumors is an independent indicator of poor prognosis (4)(5)(6)(7)(8). Here, we found that high PAI1 mRNA expression is also associated with shorter overall survival in breast cancer.…”

Section: Discussionsupporting

confidence: 59%

“…High tumoral PAI1 protein expression is associated with poor survival in several forms of cancer (1)(2)(3) and is a strong independent prognostic factor in breast cancer, with elevated levels forecasting shorter recurrence-free and overall survival (4)(5)(6)(7)(8). In addition, prospective data suggest that high tumoral PAI1 levels can identify those lymph node-negative (LN − ) breast cancer patients who are most likely to benefit from adjuvant chemotherapy (9,10).…”

Section: Introductionmentioning

confidence: 99%

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Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression

Sternlicht¹,

Dunning

Moore

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Plasminogen activator inhibitor-1 (PAI1) can promote cancer progression, and its protein expression in tumors is an independent indicator of poor prognosis in many forms of cancer. Here, we show that high PAI1 mRNA levels also predict for shorter overall survival in two independent breast cancer data sets, highlighting the importance of its transcriptional regulation. The −675insG (4G/5G) singlenucleotide polymorphism in the PAI1 gene promoter has been shown to influence PAI1 transcription, with the 4G allele eliciting higher reporter gene expression in vitro and higher levels of circulating PAI1 in vivo. Nevertheless, its genotypic distribution in 2,539 British women with invasive breast cancer was virtually identical to that seen in 1,832 matched controls (P = 0.72), and annual mortality rates for 4G4G, 4G5G, and 5G5G cases were 2.6%, 2.8%, and 3.1% per year, respectively (P = 0.10). Thus, there was no association with breast cancer incidence or outcome, and in a separate set of breast cancers, the 4G/5G single-nucleotide polymorphism showed no association with PAI1 mRNA expression (P = 0.85). By contrast, connective tissue growth factor (CTGF), which can regulate PAI1 expression in culture, was associated with PAI1 expression in three independent cohorts (P ≪ 0.0001). In addition, PAI1 gene copy number differences in the tumors were correlated with PAI1 mRNA expression (P = 0.0005) and seemed to affect expression independently of CTGF. Thus, local factors, such as CTGF and genomic amplification, seem to be more important than germ line genetic variation in influencing PAI1 expression and its untoward effects in breast cancer.Requests for reprints:

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression

Sternlicht¹,

Dunning

Moore

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…For example, numerous studies have shown that patients with breast cancer and low levels of uPA and PAI-1 have a significantly better survival than patients with high levels of either factor. The particular combination of both factors, uPA/PAI-1 (both low vs either or both factors high), outperforms the single factors as well as other traditional prognostic factors with regard to risk group assessment, particularly in node-negative breast cancer (Harbeck et al, 2002). Another case in point is the tumor cell-selective cytotoxicity of MMP-activated anthrax toxin (Liu et al, 2000;Koo et al, 2002).…”

Section: Clinical Applicationsmentioning

confidence: 99%

Axis of evil: molecular mechanisms of cancer metastasis

2003

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Although the genetic basis of tumorigenesis may vary greatly between different cancer types, the cellular and molecular steps required for metastasis are similar for all cancer cells. Not surprisingly, the molecular mechanisms that propel invasive growth and metastasis are also found in embryonic development, and to a less perpetual extent, in adult tissue repair processes. It is increasingly apparent that the stromal microenvironment, in which neoplastic cells develop, profoundly influences many steps of cancer progression, including the ability of tumor cells to metastasize. In carcinomas, the influences of the microenvironment are mediated, in large part, by bidirectional interactions (adhesion, survival, proteolysis, migration, immune escape mechanisms lymph-/angiogenesis, and homing on target organs) between epithelial tumor cells and neighboring stromal cells, such as fibroblasts as well as endothelial and immune cells. In this review, we summarize recent advances in understanding the molecular mechanisms that govern this frequently lethal metastatic progression along an axis from primary tumor to regional lymph nodes to distant organ sites. Affected proteins include growth factor signaling molecules, chemokines, cell-cell adhesion molecules (cadherins, integrins) as well as extracellular proteases (matrix metalloproteinases). We then discuss promising new therapeutic approaches targeting the microenvironment. We note, however, that there is still too little knowledge of how the many events are coordinated and integrated by the cancer cell, with conspiratorial help by the stromal component of the host. Before drug development can proceed with a legitimate chance of success, significant gaps in basic knowledge need to be filled.

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“…HER2/neu protein level and (or gene amplification) has proven to be important for selection of patients for specific treatment (29). Recently, meta-analysis of proteins of the plasminogen activator system has shown that high levels of uPA and PAI-1 are predictive for disease recurrence in patients with early breast cancer (17,18,30). The prognostic value of most novel markers appears insufficient to justify its single use in diagnosis.…”

Section: Discussionmentioning

confidence: 99%

The Prognostic Value of BCAR1 in Patients with Primary Breast Cancer

Dorssers

Grebenchtchikov

Brinkman

et al. 2004

Clinical Cancer Research

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Purpose: BCAR1, the human homologue of the rat p130Cas protein, was identified in a functional screen for human breast cancer cell proliferation resistant to antiestrogen drugs. Here, we study the prognostic value of quantitative BCAR1 levels in a large series of breast cancer specimens.Experimental Design: A specific ELISA was developed to measure BCAR1 protein levels in 2593 primary breast tumor cytosols. Tumor levels of BCAR1 were correlated with relapse-free survival (RFS) and overall survival (OS) and compared with collected data on urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1).Results: In tumor cytosols, BCAR1 protein levels varied between 0.02 and 23 ng/mg protein. BCAR1 levels exhibited a positive correlation with steroid hormone receptor levels, age and menopausal status, and uPA and PAI-1 levels. The level of BCAR1 (continuous or categorized as low, intermediate, or high) was inversely related with RFS and OS time. Multivariate analysis showed that BCAR1 levels contributed independently to a base model containing the traditional prognostic factors for both RFS and OS (both P < 0.0001).When added together with uPA and PAI-1 in the multivariate model, BCAR1 contributed independently of PAI-1 and was favored over uPA. Interaction tests allowed for additional analyses of BCAR1 protein levels in clinically relevant subgroups stratified by nodal and menopausal status.Conclusions: The quantitative BCAR1 protein level represents a prognostic factor for RFS and OS in primary breast cancer, independent of the traditional prognostic factors and the other novel marker PAI-1.

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Clinical Utility of Urokinase-Type Plasminogen Activator and Plasminogen Activator Inhibitor—1 Determination in Primary Breast Cancer Tissue for Individualized Therapy Concepts

Cited by 66 publications

References 30 publications

Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression

Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression

Axis of evil: molecular mechanisms of cancer metastasis

The Prognostic Value of BCAR1 in Patients with Primary Breast Cancer

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