Prognostic value of PAI1 in invasive breast cancer: Evidence that tumor-specific factors are more important than genetic variation in regulating PAI1 expression

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.