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This Article Full Text Full Text (PDF) 082800.Supplemental Data All Versions of this Article: clinchem.2006.082800v1 53/7/1280    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Sieuwerts, A. M. Articles by Foekens, J. A. Search for Related Content PubMed PubMed Citation Articles by Sieuwerts, A. M. Articles by Foekens, J. A. Related Collections Cancer Diagnostics (since 2002)

Concentrations of TIMP1 mRNA Splice Variants and TIMP-1 Protein Are Differentially Associated with Prognosis in Primary Breast Cancer

¹ Department of Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
² Department of Veterinary Pathobiology, Faculty of Life Sciences, University of Copenhagen, Copenhagen, Frederiksberg C, Denmark.

^aAddress correspondence to this author at: Erasmus MC, Josephine Nefkens Institute, Rm. Be 400, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Fax 31-10-408-8377; e-mail a.sieuwerts{at}erasmusmc.nl.

Background: TIMP-1 protein is a prognostic factor for recurrence-free and overall survival (OS) time in breast cancer. We evaluated the prognostic value of TIMP1 mRNA and a novel TIMP1 mRNA splice variant in 1301 primary breast cancer patients.

Methods: We measured mRNA transcripts of full-length TIMP1 (TIMP1-v1) and the novel splice variant lacking exon 2 (TIMP1-v2) by use of real-time RT-PCR in frozen primary tumor samples. Transcript concentrations are correlated with histomorphological and biological factors, TIMP-1 protein, and distant metastasis-free survival (MFS) and OS time.

Results: TIMP1-v1 and TIMP1-v2 alone were not informative with respect to predicting prognosis. However, the PCR assay designed to measure the combination of v1 + v2 showed that high concentrations of this combination were associated with good prognosis. In Cox multivariate regression analysis, which also included the traditional prognostic factors, increasing concentrations were independently associated with prolonged MFS (P = 0.004) and OS (P = 0.048). Including TIMP-1 protein and TIMP1-v1+v2 mRNA together in the multivariate model revealed that protein and mRNA were both independently associated with prognosis, with hazard ratios pointing in opposite directions.

Conclusion: High concentrations of TIMP1-v1+2 mRNA are associated with good prognosis in patients with primary breast cancer. Since high concentrations of TIMP-1 protein are associated with poor prognosis, the presence of possible posttranscriptional mechanisms requires further investigation.

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