Association ofMatrix Metalloproteinase-8Gene Variation with Breast Cancer Prognosis

Abstract

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 f1,100 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 tumornode-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.

Collagenase-2 (matrix metalloproteinase-8) plays a protective role in tongue cancer

“…By contrast, parallel analysis with MMP-8 revealed that production of this protease was significantly associated with good clinical outcome in tongue cancer patients. Decock et al (2007) showed that genetic variation in the MMP-8 gene could influence breast cancer prognosis. They also noticed that MMP-8 inhibited breast cancer metastasis.…”

The Contribution of Matrix Metalloproteinase-8 Promoter Polymorphism to Oral Cancer Susceptibility

“…Secondly, in two cell lines derived from wild-type MDA-MB-435 cancer cells, which display high (M-4A4) or low (NM-2C5) metastatic capacities, overexpression of MMP-8 would reduce the metastatic capacity of M-4A4 cells, whereas knockdown of MMP-8 gene would enhance the metastatic capacity of NM-2C5 cells (26,27). Thirdly, the rs11225395 C-799T single-nucleotide polymorphism (SNP) at the MMP8 promoter region may affect the expression levels of MMP-8 and associate with early-stage disease (28). Fourthly, higher MMP8 mRNA levels in primary breast cancers are associated with reduced lymph node metastasis and with improved relapse-free and overall survival in nodenegative patients (29).…”

Genetic polymorphism of matrix metalloproteinases in breast cancer

“…However, a correlation has been shown to occur between lymph node metastasis and four SNPs rs1940475 G allele (p = 0.03), rs1892986 A allele (p = 0.03), rs1276284 A allele (p = 0.03), rs11225395 T allele (p = 0.02). Decock et al also using blood samples from breast cancer patients from an extensive database (Shanghai Breast Cancer Study) have confirmed that the MMP-8 (rs11225395) with T allele is associated with lower frequency of metastasis to lymph nodes compared with C allele and with longer survival of patients with early stage cancer [50].…”