Polymorphisms of the promoter regions of matrix metalloproteinases genes MMP-1 and MMP-9 in breast cancer
- 228 Downloads
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.
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.
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.
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.
Key words:breast cancer gene polymorphism matrix metalloproteinases (MMPs) MMP-1 gene MMP-9 gene tumour progression
Unable to display preview. Download preview PDF.
This work was supported by the grants 6P05A 045 21 from KBN (KP) and 505/363 from University of Lodz (JB).
- 5.Nikkola J, Vihinen P, Vuoristo MS, Kellokumpu-Lehtinen P, Kahari VM, Pyrhonen S: High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma. Clin Cancer Res 11(14): 5158–5166, 2005Google Scholar
- 16.Kanamori Y, Matsushima M, Minaguchi T, Kobayashi K, Sagae S, Kudo R, Terakawa N, Nakamura Y: Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region. Cancer Res 59(17): 4225–4227, 1999Google Scholar
- 21.Iwata H., Kobayashi S., Iwase H., Masaoka A., Fujimoto N., Okada Y, Production of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human breast carcinomas Jpn J Cancer Res 1999;87:602–611Google Scholar
- 22.Itoh F., Yamamoto H., Hinoda Y., Imai K, Enhanced secretion and activation of ,matrylisin during malignant conversion of human colorectal epithelium and its relationship with invasive potential of colon cancer cells Cancer (Phila.) 1996;77:1717–1721Google Scholar
- 24.Balduyck M, Zerimech F, Gouyer V, Lemaire R, Hemon B, Grard G, Thiebaut C, Lemaire V, Dacquembronne E, Duhem T, Lebrun A, Dejonghe MJ, Huet G, Specific expression of matrix metalloproteinases 1, 3, 9 and 13 associated with invasiveness of breast cancer cells in vitro Clin Exp Metastasis 18:171–178, 2000CrossRefPubMedGoogle Scholar
- 25.Biondi ML, Turri O, Leviti S, Seminati R, Cecchini F, Bernini M, Ghilardi G, Guagnellini E: MMP1 and MMP3 polymorphisms in promoter regions and cancer. Clin Chem. 46 (12): 2023–2024, 2000Google Scholar
- 26.Ghilardi G, Biondi ML, Caputo M, Leviti S, DeMonti M, Guagnellini E, Scorza R: A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter enhances breast cancer susceptibility Clin Cancer Res 8(12): 3820–3823, 2002Google Scholar
- 29.Li HC, Cao DC, Liu Y, Hou YF, Wu J, Lu JS, Di GH, Liu G, Li FM, Ou ZL, Jie C, Shen ZZ, Shao ZM: Prognostic value of matrix metalloproteinases (MMP-2 and MMP-9) in patients with lymph node-negative breast carcinoma. Breast Cancer Res Treat 88(1): 75–85, 2004Google Scholar
- 31.Goto F, Goto K, Weindel K, Folkman Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial. cells within collagen gels J Lab Invest 1993;69:508–517Google Scholar