Plasminogen activator inhibitor-1 4G/5G polymorphism in breast cancer patients and its association with tissue PAI-1 levels and tumor severity

Castelló, Remedios; España, Francisco; Vázquez, Carlos; Fuster, Carlos; Almenar, S.; Aznar, Justo; Estellés, Amparo

doi:10.1016/j.thromres.2005.03.025

Cited by 36 publications

(28 citation statements)

References 34 publications

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“…A recent study reported that 3) P = 0.0001, log-rank P < 0.0001, log-rank the PAI-1 4G allele was associated with high tissue levels of PAI-1 and less favorable characteristics of breast cancer (such as an advanced histologic grade), a finding that is in line with our results (21). However, in an earlier study of breast cancer patients, no association was found between PAI-1 4G/5G genotype and lymph node status (22).…”

Section: Discussionsupporting

confidence: 92%

Functional Plasminogen Activator Inhibitor-1 Gene Variants and Breast Cancer Survival

Zhang

Shu

Cai

et al. 2006

Clinical Cancer Research

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Purpose: Plasminogen activator inhibitor-1 (PAI-1) plays an important role in cancer invasion and metastasis. A common polymorphism (4G/5G) in the promoter region of the PAI-1 gene has been reported to influence transcription and plasma levels of PAI-1. We evaluated the association between PAI-1 4G/5G polymorphism and breast cancer survival in a population-based cohort of breast cancer patients. Experimental Design: Included in this analysis were 1,083 Chinese women diagnosed with stage 0 to III primary breast cancer at age 25 to 64 years who were recruited between 1996 and 1998 for the Shanghai Breast Cancer Study and followed for a median of 5.2 years. The KaplanMeier method and Cox model were used to evaluate the genotype and survival association. Results: After adjustment for known prognostic factors for breast cancer, patients homozygous for the 4G allele had significantly poorer disease-free survival [hazard ratio (HR), 1.7; 95% confidence interval (95% CI), 1.1-2.4] and overall survival (HR, 1.5; 95% CI, 1.0-2.3) than those homozygous for the 5G allele. The association was more evident in patients with advanced disease. The HRs (95% CI) were 3.5 (1.4-9.0) for disease-free survival and 3.1 (1.1-8.3) for overall survival in stage III patients. Conclusions: The PAI-1 4G/5G polymorphism may be a prognostic marker for young and middle-aged Chinese breast cancer patients.Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor superfamily, is a key regulator of extracellular matrix homeostasis, protecting the extracellular matrix from excessive degradation (1). PAI-1 also interacts with the extracellular matrix component vitronectin and thus is believed to be a molecular switch that governs cell adhesion and migration (2, 3). Given these biological properties, it is hypothesized that PAI-1 may play an important role in cancer invasion and metastasis (1). In support of this hypothesis, high tissue levels of PAI-1 have been consistently reported to predict poor prognosis in several types of human cancers, including breast cancer (1,4,5).The human PAI-1 gene is located on chromosome 7 (6). A common single-bp insertion/deletion polymorphism (4G/5G) has been reported in the promoter region of the PAI-1 gene, 675 bp upstream of the transcriptional start site (6, 7). This polymorphism affects the binding of transcription factors; a repressor protein binds to the promoter with the 5G allele but not to the promoter with the 4G allele (6 -9). Studies in different populations, including the Chinese, have shown consistently that subjects homozygous for the 4G allele have significantly higher plasma PAI-1 levels than those homozygous for the 5G allele (6, 10, 11).The 4G/5G polymorphism of the PAI-1 gene has been extensively studied for associations with cardiovascular disease (6,7,9,12); little research, however, has been conducted on its association with cancer. We evaluated the association between PAI-1 4G/5G polymorphism and breast cancer survival in 1,083 breast cancer patients who p...

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Section: Discussionsupporting

confidence: 92%

Functional Plasminogen Activator Inhibitor-1 Gene Variants and Breast Cancer Survival

Zhang

Shu

Cai

et al. 2006

Clinical Cancer Research

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“…Likewise, it is unclear whether the 4G/5G SNP has any appreciable affect on tumoral PAI1 levels or whether it is overpowered by other factors. One study found no association between the 4G/5G SNP and PAI protein levels in 40 colorectal cancers (50), whereas another found that the high-expressing 4G allele was associated with increased tumoral PAI1 expression in 104 breast cancers (40). Our own analyses revealed no such association in a subset of UCSF breast cancers, which is consistent with the lack of association between the 4G/5G SNP and outcome in the SEARCH and UCSF cohorts.…”

Section: Discussionsupporting

confidence: 78%

“…By comparison, the five other studies that have examined this SNP in cancer had an average of only 92 cases and 122 controls per study and were thus far less apt to detect a true association (40)(41)(42)(43)(44). Despite or due to their limited size, three of these studies detected borderline associations between the high-expressing 4G allele and breast (40,41) or general cancer incidence (42), whereas no associations were seen in ovarian (43) or colorectal cancer (44). In both breast cancer studies, the 4G allele was more common among cases than controls, and 4G carriers were more apt to have cancer than 5G homozygotes, particularly when the studies were combined.…”

Section: Discussionmentioning

confidence: 95%

“…The high-expressing 4G4G genotype has also been associated with more advanced colorectal cancers (44) as well as larger diameter and higher-grade breast cancers (40), whereas no such associations were seen in another breast cancer cohort (41). Indeed, these few significant associations are outnumbered by multiple null comparisons and were seen in subsets with an average of only 38 cases (range = 17-55), thus increasing the likelihood that they represent false-positive associations.…”

Section: Discussionmentioning

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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“…In breast cancer, tumor severity may be associated with polymorphism of the plasminogen activator inhibitor type 1 4G/5G gene (45). In addition, uPA has been revealed to be associated with poor patient prognosis and tumor metastasis in breast cancer via various signaling pathways, including extracellular matrix breakdown (46).…”

Section: Discussionmentioning

confidence: 99%

Microarray based analysis of gene regulation by mesenchymal stem cells in breast cancer

Zhang

Gao

et al. 2017

Oncology Letters

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Abstract. Breast cancer is one of the most common malignant tumors with a high case-fatality rate among women. The present study aimed to investigate the effects of mesenchymal stem cells (MSCs) on breast cancer by exploring the potential underlying molecular mechanisms. The expression profile of GSE43306, which refers to MDA-MB-231 cells with or without a 1:1 ratio of MSCs, was downloaded from Gene Expression Omnibus database for differentially expressed gene (DEG) screening. The Database for Annotation, Visualization and Integrated Discovery was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs. The protein-protein interactional (PPI) network of DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins. The data was subsequently analyzed using molecular complex detection for sub-network mining of modules. Finally, DEGs in modules were analyzed using GO and KEGG pathway enrichment analyses. A total of 291 DEGs including 193 upregulated and 98 downregulated DEGs were obtained. Upregulated DEGs were primarily enriched in pathways including response to wounding (P=5.92x10 -7 ), inflammatory response (P=5.92x10 ). The PPI network, which contained 156 nodes and 289 edges, was constructed, and Fos was the hub node with the degree of 29. A total of 3 modules were mined from the PPI network. In total, 14 DEGs in module A were primarily enriched in GO terms, including response to wounding (P=4.77x10 -6 ), wounding healing (P=6.25x10 -7 ) and coagulation (P=1.13 x10 -7 ), and these DEGs were also enriched in 1 KEGG pathway (complement and coagulation cascades; P=0.0036). Therefore, MSCs were demonstrated to exhibit potentially beneficial effects for breast cancer therapy. In addition, the screened DEGs, particularly in PPI network modules, including FN1, CD44, NGF, SERPINE1 and CCNA2, may be the potential target genes of MSC therapy for breast cancer.

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Plasminogen activator inhibitor-1 4G/5G polymorphism in breast cancer patients and its association with tissue PAI-1 levels and tumor severity

Cited by 36 publications

References 34 publications

Functional Plasminogen Activator Inhibitor-1 Gene Variants and Breast Cancer Survival

Functional Plasminogen Activator Inhibitor-1 Gene Variants and Breast Cancer Survival

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

Microarray based analysis of gene regulation by mesenchymal stem cells in breast cancer

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