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Association of Matrix Metalloproteinase-8 Gene Variation with Breast Cancer Prognosis

¹ Laboratory for Experimental Oncology, Department of General Medical Oncology, University Hospital Gasthuisberg, Leuven, Belgium; ² Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, University of London, London, United Kingdom; ³ Human Genetics Division, University of Southampton School of Medicine, Southampton, United Kingdom; ⁴ Faculdade de Odontologia de São José dos Campos–Universidade Estadual Paulista, Departamento de Biociencias e Diagnostico Bucal, Brazil; ⁵ Department of Medicine, Vanderbilt Epidemiology Centre, Vanderbilt–Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; and ⁶ Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China

Requests for reprints: Shu Ye, William Harvey Research Institute, John Vane Science Building, Charthouse Square, London EC1M 6BQ, United Kingdom. Phone: 44-207-882-3425; Fax: 44-207-882-3408; E-mail: s.ye{at}qmul.ac.uk and Wei Zheng, Vanderbilt Epidemiology Centre, 2525 West End Avenue, 8th floor, Nashville, TN 37203. Phone: 615-936-0682; Fax: 615-936-8241; E-mail: wei.zheng{at}vanderbilt.edu.

Animal and cell studies indicate an inhibitory effect of matrix metalloproteinase-8 (MMP8) on tumorigenesis and metastasis. We investigated whether MMP8 gene variation was associated with breast cancer metastasis and prognosis in humans. We first studied nine tagging single nucleotide polymorphisms (SNP) in the MMP8 gene in 140 clinically and pathologically well-characterized breast cancer patients. Four of the SNPs were found to be associated with lymph node metastasis, the most pronounced being a promoter SNP (rs11225395) with its minor allele (T) associating with reduced susceptibility to lymph node metastasis (P = 0.02). This SNP was further evaluated for association with cancer relapse and survival among a cohort of 1,100 breast cancer patients who had been followed for cancer recurrence and mortality for a median of 7.1 years. The T allele was associated with reduced cancer relapse and greater survival, particularly among patients with earlier stage cancer. Among patients of tumor-node-metastasis stage 0 to II, the adjusted hazard ratio of disease-free survival was 0.7 [95% confidence interval (95% CI), 0.5–0.9] for patients carrying T allele compared with those homozygous for the C allele (P = 0.02). In vitro experiments showed that the T allele had higher promoter activity than the C allele in breast cancer cells. Electrophoretic mobility shift assays showed binding of nuclear proteins to the DNA sequence at the SNP site of the T allele but not that of the C allele. The data suggest that MMP8 gene variation may influence breast cancer prognosis and support the notion that MMP8 has an inhibitory effect on cancer metastasis. [Cancer Res 2007;67(21):10214–21]

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