Sternlicht Mark D, Dunning Alison M, Moore Dan H, Pharoah Paul D P, Ginzinger David G, Chin Koei, Gray Joe W, Waldman Frederic M, Ponder Bruce A J, Werb Zena
Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, HSW-1301 San Francisco, CA 94143-0452, USA.
Cancer Epidemiol Biomarkers Prev. 2006 Nov;15(11):2107-14. doi: 10.1158/1055-9965.EPI-06-0351.
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.
纤溶酶原激活物抑制剂-1（PAI1）可促进癌症进展，其在肿瘤中的蛋白表达是多种癌症预后不良的独立指标。在此，我们表明，在两个独立的乳腺癌数据集中，PAI1 mRNA高水平也预示着总生存期较短，凸显了其转录调控的重要性。PAI1基因启动子中的-675insG（4G/5G）单核苷酸多态性已被证明会影响PAI1转录，4G等位基因在体外可引发更高的报告基因表达，在体内可导致循环PAI1水平升高。然而，在2539名患有浸润性乳腺癌的英国女性中，其基因型分布与1832名匹配对照者几乎相同（P = 0.72），4G4G、4G5G和5G5G病例的年死亡率分别为每年2.6%、2.8%和3.1%（P = 0.10）。因此，其与乳腺癌发病率或预后无关，在另一组乳腺癌中，4G/5G单核苷酸多态性与PAI1 mRNA表达无关（P = 0.85）。相比之下，可在培养中调节PAI1表达的结缔组织生长因子（CTGF）在三个独立队列中与PAI1表达相关（P << 0.0001）。此外，肿瘤中PAI1基因拷贝数差异与PAI1 mRNA表达相关（P = 0.0005），且似乎独立于CTGF影响表达。因此，在影响PAI1表达及其在乳腺癌中的不良作用方面，局部因素如CTGF和基因组扩增似乎比种系基因变异更重要。
