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

Abstract

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...

PAI-1 −675 4G/5G polymorphism as a prognostic biomarker in breast cancer

“…The first one, carried out among 1,083 Chinese women diagnosed with breast cancer within the Shanghai Breast Cancer Study, observed both worse disease-free and overall survival in patients homozygous for the 4G allele [32]. The effect was more evident in patients with advanced disease [32]. The results from our study on 959 Swedish breast cancer cases showed an opposite effect with a much worse survival for the 5G/5G genotype carriers.…”

“…In another small study on 28 tumor samples from Spain, the 5G/5G homozygosity associated significantly with the presence of the uPA:PAI-1 complex inside the tumor cells and marginally with a less aggressive, better-differentiated tumor phenotype [27]. Recently, two large studies have investigated the effects of the PAI-1 4G/5G SNP on breast cancer [31,32]. The first one, carried out among 1,083 Chinese women diagnosed with breast cancer within the Shanghai Breast Cancer Study, observed both worse disease-free and overall survival in patients homozygous for the 4G allele [32].…”

“…Recently, two large studies have investigated the effects of the PAI-1 4G/5G SNP on breast cancer [31,32]. The first one, carried out among 1,083 Chinese women diagnosed with breast cancer within the Shanghai Breast Cancer Study, observed both worse disease-free and overall survival in patients homozygous for the 4G allele [32]. The effect was more evident in patients with advanced disease [32].…”

Assessment of Urokinase-Type Plasminogen Activator and Its Inhibitor PAI-1 in Breast Cancer Tissue: Historical Aspects and Future Prospects

“…Although still a matter of debate, especially for PAI-1, transcription can also be influenced by genetic factors leading to nucleotide polymorphisms (e.g. 4G/5G) of the PAI-1 gene [63,64]. In contrast to these studies, Sternlicht et al [65], screening more than 2500 tumour tissue samples of breast cancer patients, did not find such an association of PAI-1 polymorphism with mRNA levels and frequency differences between tumour and control collectives, and also no association with annual mortality rates between the different allele subsets.…”

Clinical impact of PAI 1 4G/5G gene polymorphism in colorectal carcinoma patients

“…Castelló et al and Zhang et al in their group of patients showed a greater likelihood of lymph node involvement in patients with breast cancer with the 4G/4G genotype, and thus worse prognosis [27,55]. Lei et al on the contrary, in his research showed a worse prognosis in patients with 5G/5G genotype [56].…”