Elsevier

Thrombosis Research

Volume 124, Issue 4, September 2009, Pages 403-408
Thrombosis Research

Regular Article
Prognostic value of pre-surgical plasma PAI-1 (plasminogen activator inhibitor-1) levels in breast cancer

https://doi.org/10.1016/j.thromres.2009.02.014Get rights and content

Abstract

Introduction

Plasminogen activator inhibitor (PAI-1) may have an independent prognostic value in breast cancer (BC). PAI-1 4G/5G polymorphism may have significance for antigen expression. Thus, we analyzed the possible associations between PAI-1 4G/5G polymorphism, plasma PAI-1 levels, and clinicopathological features of breast cancer (BC) patients.

Patients and Methods

PAI-1 4G/5G polymorphism (both on germinal and tumor DNA) and plasma PAI-1 levels were investigated in 99 BC patients and 50 unrelated healthy women similar for age and menopausal status.

Results

No association was found between allele frequencies and clinicopathological features of BC or plasma antigen levels. Plasma PAI-1 levels were higher in BC compared to controls (p = 0.002), particularly in patients with large tumors (p < 0.001). 5-year follow-up was achieved in 79 patients: 30% had relapsing disease, 63% with positive compared to 37% with negative PAI-1 levels (p < 0.05). 5-year relapse-free survival rate of positive PAI-1 was 46% vs., 77% of negative patients (p = 0.02).

Conclusions

We may conclude that plasma PAI-1 levels in BC patients could represent a useful prognostic variable for relapse, although PAI-1 polymorphism might not represent a genetic susceptibility factor.

Introduction

Tumor cell invasion and metastasis depend on the coordinated and temporal expression of proteolytic enzymes to degrade the surrounding extracellular matrix and of adhesion molecules to remodel cell-cell and/or cell-matrix attachments [1]. Plasminogen activator inhibitor-1 (PAI-1) is a multifaceted proteolytic factor that plays an important role in signal transduction, cell adherence and cell migration, thus promoting invasion and metastasis [2]. Accordingly, PAI-1 concentrations and mRNA levels in primary tumor tissues correlate with adverse patient outcome in multiple cancer types, including breast cancer (BC)[3], [4], [5], [6], [7], [8].

Gene variability could contribute to the level of the PAI-1 biosynthesis. Among the variants of the PAI-1 gene, the insertion (5G)/deletion (4G) polymorphism has been the most frequently studied, because its location at the promoter of the gene indicates its possible role in the regulation of PAI-1 transcription. Recent data suggested that genotyping PAI-1 4G/5G may help in clinical prognosis of BC, but results are contradictory. Although few studies suggested that 4G/4G homozygosity is associated with elevated tissue PAI-1 levels [9] node-positive BC [10], and poor relapse-free (RFS) and overall (OS) survival [11], others suggested an involvement of 5G/5G homozygosity, especially among node negative patients [12], or denied any association between the polymorphism and BC invasiveness [8], [13].

PAI-1 4G/5G polymorphism is a mononucleotide repetitive DNA sequence. Tumor nucleic acid variations in the length of repetitive sequence, due to mutations in mismatch repair genes, are strictly related to neoplastic transformation of human BC [14]. Thus, we sought to investigate whether variations might occur in the allele frequency between germinal and tumor DNAs. The influence of PAI-1 4G/5G polymorphism on plasma PAI-1 levels and their possible associations with clinicopathological features of BC were also analyzed. In addition, a follow-up study was performed to evaluate the possible prognostic value of these variables in predicting the RFS of patients with BC.

Section snippets

Patients' information

Ninety-nine women with primary BC, enrolled at Tor Vergata Clinical Center, were included into the study. BC was pathologically staged according to the TNM classification. All patients underwent surgery for their primary tumor. Adjuvant chemotherapy regimens were instituted in 71 (72%) women, 43 with and 28 without lymph node involvement. Adjuvant chemotherapies were anthracycline containing (n = 61) and non-anthracycline (n = 10) containing regimens. First-line chemotherapy was instituted in one

Results

Based on molecular studies, all BC and control women were divided into three genotypes of the PAI-1 gene promoter region: 4G/4G, 4G/5G and 5G/5G. Genotype distribution of BC patients (26%, 44% and 30%, respectively) and controls (20%, 58% and 22%, respectively) did not differ significantly from those predicted by the Hardy-Weinberg distribution (HW probability test = 0.743 for BC patients). Additionally, the frequencies of the 4G and 5G alleles did not significantly differ between BC patients (4G =

Discussion

PAI-1 protein expression in tumors is an independent indicator of poor prognosis in BC [3], [4] and it has been demonstrated that high tumor tissue PAI-1 levels can identify those lymph node negative BC patients who are most likely to benefit from adjuvant chemotherapy [5], [6], [7]. Nevertheless, tumor PAI-1 expression is rarely used in clinical decision making, as the protein-based assays used to establish its prognostic and predictive value are poorly adapted to the limited amounts of tissue

Conflict of interest statement

None.

Acknowledgements

The authors wish to thank Prof. Giovanni Destro Bisol for helping in genetic association analyses and for critically revising the manuscript. Thanks also to Marco Ciancia, Barbara Leone and Isabella Lucci for their excellent technical assistance. Partially supported by the Italian Ministry of Health Research Grant, Finalized Project - RF03.83.

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