Polymorphisms of the promoter regions of matrix metalloproteinases genes MMP-1 and MMP-9 in breast cancer.
OBJECTIVE
Matrix metalloproteinases play a crucial role in the cancer invasion and metastasis, angiogenesis and tumorigenicity. A single guanine insertion--the 1G/2G polymorphism in the promoter of the matrix metalloproteinase 1 (MMP-1) gene creates a binding site for the transcription factor AP-1 and thus may affect the transcription level of MMP-1. The C-->T substitution at the polymorphic site of the MMP-9 gene promoter results in a higher transcription activity of the T-allelic promoter trough the loss of binding site for a repressor protein. The aim of this work was to investigate the influence of 1G/2G and C-->T polymorphisms on the MMP-1 and MMP-9 level and therefore on the occurrence and progression of breast cancer.


METHODS
We investigated the distribution of genotypes and frequency of alleles of the 1G/2G and C-->T polymorphisms for 270 patients with breast cancer and 300 healthy women served as control. The genotypes were determined by RFLP-PCR. Additionally, we estimated the level of MMP-1 and MMP-9 antigens in tumor samples and normal breast tissue using ELISA.


RESULTS
The levels of MMP-1 in tumor samples of node positive patients ware significantly higher than in samples of node negative patients (p<0.05). Increased level of MMP-9 correlates with Bloom-Richardson grading III (p<0.05), increased tumor size (p<0.05) and absence of estrogen and progesterone receptors (p<0.01). Additionally, both MMP-1 and MMP-9 levels were higher in tumor than in the normal breast tissue. We showed the higher risk of metastasis development in lymph node for the 2G/2G genotype (OR=2.14; CI 95% 1.24;3.69) and the 2G allele carriers (OR=1.68; CI 95% 1.19;2.39). We found correlation between the T allele (OR=2.61; CI 95% 1.33;4.87), 2G (OR=2.58; CI 95% 1.35;4.91) and malignance.


CONCLUSIONS
The results suggest that MMP-1 is responsible for the local invasion and MMP-9 is associated with the malignance and the growth of the tumor. We suggest that the 2G allele of the 1G/2G MMP-1 gene polymorphism may be associated with the lymph node metastasis in patients with breast cancer and therefore it can be considered as a progression marker in this disease.
Przybylowska
Karolina
K
Department of Molecular Genetics, University of Lodz, Lodz, Poland.
Kluczna
Anita
A
Zadrozny
Marek
M
Krawczyk
Tadeusz
T
Kulig
Andrzej
A
Rykala
Jan
J
Kolacinska
Agnieszka
A
Morawiec
Zbigniew
Z
Drzewoski
Jozef
J
Blasiak
Janusz
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic
D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1