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Matrix Metalloproteinase Single-Nucleotide Polymorphisms and Haplotypes Predict Breast Cancer Progression

Authors' Affiliations: ¹ Tumour Biology Laboratory and ² Cancer Research UK Centre for Epidemiology, Wolfson Institute of Preventive Medicine, Cancer Research UK Clinical Centre, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom and ³ Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom

Requests for reprints: J. Louise Jones, Centre for Tumour Biology, Institute of Cancer and the Cancer Research UK Clinical Centre, Barts and The London, Queen Mary's School of Medicine and Dentistry, Ground Floor, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom. Phone: 00-44-207-0140400; Fax: 00-44-207-0140401; E-mail: louise.j.jones{at}cancer.org.uk.

Purpose: Polymorphisms within the promoter region of several matrix metalloproteinase (MMP) genes have been linked to alterations in the level of transcription. We hypothesized that an individual's MMP genotype and haplotype will influence breast tumor progression and help predict prognosis.

Experimental Design: This study has evaluated the association between single-nucleotide polymorphisms (SNP) in the promoter regions of MMP-1, MMP-3, MMP-7, MMP-9, MMP-12, and MMP-13 and metastatic spread of breast cancer in 128 lymph node–negative and 93 lymph node–positive patients. The study cohort was of mixed ethnicity, with Caucasian patients comprising 65%. Associations between genotype and lymph node status were estimated by logistic regression and with overall survival using the method of Kaplan-Meier and log-rank test. Associations between haplotype and lymph node status were also investigated.

Results: The data show a significant and independent association of the C/T genotype for MMP-9 [mixed ethnicities odds ratio 3.6, 95% confidence interval (95% CI) 1.2-11.1; Caucasian odds ratio 9.1, 95% CI 1.7-48.4] and the 2G/2G genotype for MMP-1 (mixed ethnicities odds ratio 3.9, 95% CI 1.7-9.4; Caucasian odds ratio 2.6, 95% CI 1.0-6.9) with lymph node–positive disease. MMP-1 2G/2G was associated with reduced survival (hazard ratio 3.1, 95% CI 1.1-8.7), although this is dependent on lymph node status. Two haplotypes, driven by the MMP-1 2G allele, were significantly associated with lymph node–positive disease and survival.

Conclusions: These results suggest that MMP single-nucleotide polymorphisms influence breast cancer behavior and that the MMP-1 2G/2G genotype increases the risk of lymph node metastasis and predicts poor prognosis.