Promoter polymorphisms in matrix metalloproteinases and their inhibitors: few associations with breast cancer susceptibility and progression.
The importance of matrix metalloproteinases and their inhibitors in tumor progression is well documented. We wanted to investigate if single nucleotide polymorphisms (SNPs) in the promoter regions of these genes are associated with susceptibility to or progression of breast cancer. In this, so far largest case-control study, we genotyped eight SNPs in the MMP1, MMP2, MMP3, MMP9, MMP13, RECK and TIMP3 genes in a well-characterized breast cancer series of 959 cases and 952 controls from Sweden. Even though we did not correct for multiple comparisons, only a few associations were noted. We observed a moderately increased risk for the TT homozygotes of the MMP9-1562 C/T SNP (OR 1.88, 95% CI 0.97-3.63) and for the C allele carriers of the TIMP3-1296 T/C SNP (OR 1.25, 95% CI 1.05-1.50). In the survival analysis, only the TC heterozygotes of the RECK-420 T/C SNP showed a better survival compared to the TT homozygotes (P = 0.02 in all cases and P = 0.03 in lymph node negative cases). None of the other SNPs conferred an increased breast cancer risk, nor did they correlate with survival. A combination of the -585 TT homozygosity in the RECK gene and the -1296 TT homozygosity in the TIMP3 gene correlated with estrogen and progesterone receptor status (OR 1.81, 95% CI 1.03-3.21 and OR 2.10, 95% CI 1.18-3.86, respectively), and a combination of the -1306 TT homozygosity in the MMP2 gene and the -1562 CC homozygosity in the MMP9 gene with progesterone receptor status (OR 2.34, 95% CI 1.08-5.08). Although our study suggests some correlations between the studied SNPs and the progression of breast cancer, the rarity of the risk genotypes limits their usefulness in the clinic.
Lei
Haixin
H
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.
Hemminki
Kari
K
Altieri
Andrea
A
Johansson
Robert
R
Enquist
Kerstin
K
Hallmans
Göran
G
Lenner
Per
P
Försti
Asta
A
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D058851:GPI-Linked Proteins; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D013548:Sweden / Q000453:epidemiology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*
D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; C115460:RECK protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D020782:Matrix Metalloproteinases