This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Urban, P. Articles by Eppenberger-Castori, S. Search for Related Content PubMed PubMed Citation Articles by Urban, P. Articles by Eppenberger-Castori, S. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Breast Cancer Social Bookmarking                            What's this?

Increased Expression of Urokinase-Type Plasminogen Activator mRNA Determines Adverse Prognosis in ErbB2-Positive Primary Breast Cancer

From the Swiss Institute for Experimental Cancer Research, National Center of Competence in Research, Molecular Oncology; Swiss Institute of Bioinformatics; Epalinges s/Lausanne; OncoScore AG, Riehen; Department of Obstetrics and Gynaecology, University of Basel; Stiftung Tumorbank Basel, Riehen and University of Basel; Zentrum für Tumordiagnostik und Prävention, St Gallen, Switzerland; and the Buck Institute for Age Research, Novato, CA

Address reprint requests to Patrick Urban, MD, Stiftung Tumorbank Basel, Lörracherstrasse 50, CH-4125 Riehen, Switzerland; e-mail: patrick.urban{at}unibas.ch

Purpose To evaluate and validate mRNA expression markers capable of identifying patients with ErbB2-positive breast cancer associated with distant metastasis and reduced survival.

Patients and Methods Expression of 60 genes involved in breast cancer biology was assessed by quantitative real-time PCR (qrt-PCR) in 317 primary breast cancer patients and correlated with clinical outcome data. Results were validated subsequently using two previously published and publicly available microarray data sets with different patient populations comprising 295 and 286 breast cancer samples, respectively.

Results Of the 60 genes measured by qrt-PCR, urokinase-type plasminogen activator (uPA or PLAU) mRNA expression was the most significant marker associated with distant metastasis-free survival (MFS) by univariate Cox analysis in patients with ErbB2-positive tumors and an independent factor in multivariate analysis. Subsequent validation in two microarray data sets confirmed the prognostic value of uPA in ErbB2-positive tumors by both univariate and multivariate analysis. uPA mRNA expression was not significantly associated with MFS in ErbB2-negative tumors. Kaplan-Meier analysis showed in all three study populations that patients with ErbB2-positive/uPA–positive tumors exhibited significantly reduced MFS (hazard ratios [HR], 4.3; 95% CI, 1.6 to 11.8; HR, 2.7; 95% CI, 1.2 to 6.2; and, HR, 2.8; 95% CI, 1.1 to 7.1; all P < .02) as compared with the group with ErbB2-positive/uPA–negative tumors who exhibited similar outcome to those with ErbB2-negative tumors, irrespective of uPA status.

Conclusion After evaluation of 898 breast cancer patients, uPA mRNA expression emerged as a powerful prognostic indicator in ErbB2-positive tumors. These results were consistent among three independent study populations assayed by different techniques, including qrt-PCR and two microarray platforms.

Supported by the Stiftung Tumorbank Basel, the Swiss National Science Foundation (Grant No. 3100-059819.99/1), and the National Center of Competence in Research Molecular Oncology—a research instrument of the Swiss National Science Foundation. Quantitative real-time polymerase chain reaction analysis was supported by OncoScore AG.

P.U. and V.V. contributed equally to this article.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				T. van Agthoven, A. M. Sieuwerts, M. E. Meijer-van Gelder, M. P. Look, M. Smid, J. Veldscholte, S. Sleijfer, J. A. Foekens, and L. C.J. Dorssers Relevance of Breast Cancer Antiestrogen Resistance Genes in Human Breast Cancer Progression and Tamoxifen Resistance J. Clin. Oncol., February 1, 2009; 27(4): 542 - 549. [Abstract] [Full Text] [PDF]

				J. A. Foekens, A. M. Sieuwerts, M. Smid, M. P. Look, V. de Weerd, A. W. M. Boersma, J. G. M. Klijn, E. A. C. Wiemer, and J. W. M. Martens Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer PNAS, September 2, 2008; 105(35): 13021 - 13026. [Abstract] [Full Text] [PDF]

				J. Helleman, M. P.H.M. Jansen, K. Ruigrok-Ritstier, I. L. van Staveren, M. P. Look, M. E. Meijer-van Gelder, A. M. Sieuwerts, J. G.M. Klijn, S. Sleijfer, J. A. Foekens, et al. Association of an Extracellular Matrix Gene Cluster with Breast Cancer Prognosis and Endocrine Therapy Response Clin. Cancer Res., September 1, 2008; 14(17): 5555 - 5564. [Abstract] [Full Text] [PDF]

				C. Desmedt, B. Haibe-Kains, P. Wirapati, M. Buyse, D. Larsimont, G. Bontempi, M. Delorenzi, M. Piccart, and C. Sotiriou Biological Processes Associated with Breast Cancer Clinical Outcome Depend on the Molecular Subtypes Clin. Cancer Res., August 15, 2008; 14(16): 5158 - 5165. [Abstract] [Full Text] [PDF]

				I. G. Yulug and B. Gur-Dedeoglu Functional genomics in translational cancer research: focus on breast cancer Brief Funct Genomic Proteomic, March 7, 2008; (2008) eln009v1. [Abstract] [Full Text] [PDF]

				B. Du, H. Leung, K.M. F. Khan, C. G. Miller, K. Subbaramaiah, D. J. Falcone, and A. J. Dannenberg Tobacco Smoke Induces Urokinase-Type Plasminogen Activator and Cell Invasiveness: Evidence for an Epidermal Growth Factor Receptor Dependent Mechanism Cancer Res., September 15, 2007; 67(18): 8966 - 8972. [Abstract] [Full Text] [PDF]

				S. Meng, D. Tripathy, S. Shete, R. Ashfaq, H. Saboorian, B. Haley, E. Frenkel, D. Euhus, M. Leitch, C. Osborne, et al. uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues PNAS, November 14, 2006; 103(46): 17361 - 17365. [Abstract] [Full Text] [PDF]

				M. Cristofanilli and J. Mendelsohn Circulating tumor cells in breast cancer: Advanced tools for "tailored" therapy? PNAS, November 14, 2006; 103(46): 17073 - 17074. [Full Text] [PDF]