Carcinogenesis Advance Access published online on November 6, 2003
Carcinogenesis, doi:10.1093/carcin/bgh020
© 2003 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
* Corresponding author. E-mail: dlin{at}public.bta.net.cn.
Received 8 September 2003
; revised 20 October 2003
; accepted 31 October 2003
The matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) have been shown to play important role in multiple ways to all stages of cancer initiation and development. Single nucleotide polymorphisms identified in the promoters of MMP2 (-1306C
Substantial reduction in risk of breast cancer associated with genetic polymorphisms in the promoters of the matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 genes
T) and TIMP2 (-418 GC) abolish the Sp1-binding site and thus may down-regulate the expression of the genes. This case-control study was to examine the contribution of these functional polymorphisms to susceptibility to development and metastasis of breast cancer. MMP2 genotypes were determined by PCR-based denaturing high performance liquid chromatography analysis and TIMP2 genotypes identified by a PCR-RFLP method in 462 breast cancer patients and 509 frequency-matched control women. We found that the variant MMP2 genotype (-1306CT or TT) was associated with substantially reduced risk of breast cancer [odds ratio (OR), 0.46; 95% confidence interval (CI), 0.34-0.63], compared with the CC genotype. For TIMP2, a moderately reduced risk of the cancer (OR, 0.76; 95% CI, 0.58-0.99) was also associated with the variant allele (-418GC or CC), compared with the GG common allele. Furthermore, it seemed that the polymorphisms in the two genes had some additive effect and the reduced risk related to the polymorphisms appeared to be more pronounced in younger subjects. However, no significant associations were observed between the polymorphisms in the two genes and risk of tumor stage and metastasis of the cancer at the time of diagnosis. These findings suggest that the presence of the variant allele in the promoter of MMP2 or TIMP2 may be a protective factor for the development of breast cancer.
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