Association of MMP8 gene variation with breast cancer prognosis
© BioMed Central Ltd 2008
Published: 13 May 2008
Animal and cell line studies indicate an inhibitory effect of matrix metalloproteinase 8 (MMP8) on tumorigenesis and metastasis [1–3]. We investigated whether MMP8 gene variation was associated with breast cancer metastasis and prognosis in humans. We first studied nine tagging single nucleotide polymorphisms (SNPs) 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 approximately 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 tumour-node-metastasis stage 0-II, the adjusted hazard ratio of disease-free survival was 0.7 (95% CI, 0.5 to 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.
Supported by the EU Cancerdegradome Project (LSHC-CT-2003-503297), and research grants (R01CA64227 and R01CA090899) from the National Cancer Institute and CAPES/BRAZIL (PDEE 2730/05-7). The data in this abstract are presented in a manuscript accepted for publication in Cancer Research.
- Montel V, Kleeman J, Agarwal D, et al: Altered metastatic behavior of human breast cancer cells after experimental manipulation of matrix metalloproteinase 8 gene expression. Cancer Res. 2004, 64: 1687-1694. 10.1158/0008-5472.CAN-03-2047.View ArticlePubMedGoogle Scholar
- Balbin M, Fueyo A, Tester AM, et al: Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat Genet. 2003, 35: 252-257. 10.1038/ng1249.View ArticlePubMedGoogle Scholar
- Agarwal D, Goodison S, Nicholson B, et al: Expression of matrix metalloproteinase 8 (MMP-8) and tyrosinase-related protein-1 (TYRP-1) correlates with the absence of metastasis in an isogenic human breast cancer model. Differentiation. 2003, 71: 114-125. 10.1046/j.1432-0436.2003.710202.x.View ArticlePubMedGoogle Scholar