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

  • Epidemiology
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Abstract

Extracellular matrix degradation, mediated by the urokinase plasminogen activation (uPA) system, is a critical step in tumor invasion and metastasis. High tumor levels of uPA and its inhibitor PAI-1 have been correlated with poor prognosis in breast cancer. We examined whether genetic variation in the genes of the uPA system affect breast cancer susceptibility and prognosis. We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) in six genes of the uPA system in 959 Swedish breast cancer patients with detailed clinical data and up to 15 years of follow-up together with 952 matched controls. We used the unconditional logistic regression models to evaluate the associations between genotypes and breast cancer risk and tumor characteristics. The Kaplan-Meier method was used to estimate the survival probabilities; the log-rank test was used to test differences between subgroups. None of the SNPs conferred an increased breast cancer risk, but correlation with some traditional prognostic factors was observed for several SNPs. Most importantly, we identified the -675 4G/5G SNP in the PAI-1 gene as a promising prognostic biomarker for breast cancer. Compared to the 4G/4G and 4G/5G genotypes 5G/5G homozygosity correlated significantly with worse survival (RR 2.04, 95% CI 1.45–2.86, P < 0.001), especially in patients with more aggressive tumors. 5G/5G homozygotes were also the group with worse survival among lymph node negative cases. Our finding suggests that genotyping PAI-1 -675 4G/5G may help in clinical prognosis of breast cancer.

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Acknowledgments

We thank Åsa Ågren (Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Sweden) for her efficiency and skill in keeping track of samples and data. We also thank Dagmar Beiße for the technical assistance. The Northern Sweden Breast Cancer Group is appreciated for providing the clinical data. The study was supported by a grant from EU (LSHC-CT-2004-503465). The project was partially funded by Wallenberg Consortium North, Sweden.

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  1. Haixin Lei

    Present address: Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., LHRRB R505, Boston, MA, USA

Authors and Affiliations

  1. Division of Molecular Genetic Epidemiology C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany

    Haixin Lei, Kari Hemminki, Andrea Altieri & Asta Försti

  2. Center for Family and Community Medicine, Karolinska Institute, Huddinge, Sweden

    Kari Hemminki & Asta Försti

  3. Department of Oncology, Norrlands University Hospital, Umeå, Sweden

    Robert Johansson, Roger Henriksson & Per Lenner

  4. Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Umeå, Sweden

    Kerstin Enquist

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  1. Haixin Lei
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Correspondence to Asta Försti.

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Lei, H., Hemminki, K., Johansson, R. et al. PAI-1 −675 4G/5G polymorphism as a prognostic biomarker in breast cancer. Breast Cancer Res Treat 109, 165–175 (2008). https://doi.org/10.1007/s10549-007-9635-3

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  • DOI: https://doi.org/10.1007/s10549-007-9635-3

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