Regular ArticlePrognostic value of pre-surgical plasma PAI-1 (plasminogen activator inhibitor-1) levels in breast cancer☆
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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Presented at the 4th International Conference on Thrombosis and Hemostasis Issues in Cancer (ICTHIC), Bergamo, 26-28 October, 2007.