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

University of Cambridge, Cambridge, England, United Kingdom
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 12/2006; 15(11):2107-14. DOI: 10.1158/1055-9965.EPI-06-0351
Source: PubMed


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) single-nucleotide 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.

Download full-text


Available from: Mark D Sternlicht,
  • Source
    • "Plasminogen activator inhibitor-1 (PAI-1), a physiological inhibitor of urokinase-type and tissue-type plasminogen activator, is an integral part of the fibrinolytic system and contributes to the process of tumor invasion and metastasis due to degrading of the cellular matrix [43,44]. It was shown that plasma PAI-1 concentrations correlated with metastatic disease in CRC patients [45] and with the outcome of rectal cancer [46]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Obesity has been associated with increased incidence of colorectal cancer. Adipose tissue dysfunction accompanied with alterations in the release of adipocytokines has been proposed to contribute to cancer pathogenesis and progression. The aim of this study was to analyze plasma concentrations of several adipose tissue expressed hormones in colorectal cancer patients (CRC) and morbidly obese (MO) patients and to compare these concentrations to clinicopathological parameters. Methods Plasma concentrations of adiponectin, resistin, leptin, active plasminogen activator inhibitor (PAI)-1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-1 alpha, and tumor necrosis factor (TNF)-alpha were determined in 67 patients operated on for CRC (31 rectal cancers, 36 colon cancers), 37 patients operated on for morbid obesity and 60 healthy blood donors (BD). Results Compared to BD, leptin concentrations were lowered in CRC patients whereas those of MO patients were elevated. Adiponectin concentrations were only lowered in MO patients. Concentrations of MCP-1, PAI-1, and IL-1 alpha were elevated in both CRC and MO patients, while resistin and TNF-alpha were similarly expressed in MO and CRC patients compared to BD. Resistin concentrations positively correlated with tumor staging (p<0.002) and grading (p=0.015) of rectal tumor patients. Conclusions The results suggest that both MO and CRC have low-grade inflammation as part of their etiology.
    BMC Cancer 11/2012; 12(1):545. DOI:10.1186/1471-2407-12-545 · 3.36 Impact Factor
  • Source
    • "IL-6 and PAI-1 co-expression in epithelial ovarian cancer C Alberti et al signaling cascade from ligand-stimulated EGFR/MEK/ ERK or EGFR/PI3K/AKT activates the transcriptional activity of NFkB with expression of IL-6 together with PAI-1. A similar signaling pathway has been experimentally demonstrated in glioblastoma cell lines (Paugh et al., 2008), and a positive correlation between PAI-1 and IL-6 gene expression has been observed in a metaanalysis carried out on publicly available data sets of gene expression of breast carcinoma (Sternlicht et al., 2006). Interestingly, very recently ErbB2 expression, another member of the ErbB family, was found to upregulate IL-6 production through the transcriptional activity of NFkB (Hartman et al., 2011). "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "Several transcription factor binding sites for PAI-1 are found in the 5' and 3' UTR regions, and the transcriptional regulation of the gene is extremely complex [18]. Several studies have shown that SNPs within the 5'UTR lead to differences in PAI-1 expression between individuals, and this could influence the etiology of a variety of pathological conditions with which PAI-1 is associated such as cancer, rheumatoid arthritis and stroke [19-21]. We classified ONFH into two or three major subgroups based on etiology and gender: idiopathic, alcohol-induced, steroid-induced groups, and men and women. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The pathogenesis of osteonecrosis of the femoral head (ONFH) has been implicated in hypofibrinolysis and blood supply interruption. Previous studies have demonstrated that decreased fibrinolytic activity due to elevated plasminogen activator inhibitor-1 (PAI-1) levels correlates with ONFH pathogenesis. The -675 4G/5G single nucleotide polymorphism (SNP rs1799889) in the PAI-1 gene promoter is associated with PAI-1 plasma level. We investigated whether rs1799889 and two other SNPs of the PAI-1 gene (rs2227631, -844 G/A in the promoter; rs11178, +10700 C/T in the 3'UTR) are associated with increased ONFH risk. Three SNPs in PAI-1 were genotyped in 206 ONFH patients and 251 control subjects, using direct sequencing and a TaqMan® 5' allelic discrimination assay. We performed association analysis for genotyped SNPs and haplotypes with ONFH. The 4G allele of rs1799889, A allele of rs2227631, and C allele of rs11178 were significantly associated with increased ONFH risk (p = 0.03, p = 0.003, and p = 0.002, respectively). When we divided the population according to gender, an association between the three SNPs and increased risk of ONFH was found only in men. In another subgroup analysis based on the etiology of ONFH, rs2227631 (A allele) and rs11178 (C allele) in the idiopathic subgroup (p = 0.007 and p = 0.021) and rs1799889 (4G allele) and rs11178 (C allele) in the alcohol-induced subgroup (p = 0.042 and p = 0.015) were associated with increased risk of ONFH. In addition, a certain haplotype (A-4G-C) of PAI-1 was also significantly associated with ONFH (p < 0.001). Our findings demonstrated that three SNPs (rs1799889, rs2227631, and rs11178) of the PAI-1 gene were associated with ONFH risk. This study also suggests that PAI-1 SNPs may play an important role in ONFH.
    BMC Musculoskeletal Disorders 07/2011; 12(1):160. DOI:10.1186/1471-2474-12-160 · 1.72 Impact Factor
Show more