Abstract
Matrix metalloproteinases (MMPs) are proteolytic enzymes that play important roles in tumor invasion and metastasis by degrading extracellular matrix components. Genetic variations in promoter regions of MMP genes, affecting their expression, have been associated with susceptibility to cancers. The aim of this study was to investigate the susceptibility and prognostic implications of the matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) polymorphism in Tunisian breast cancer patients. MMP-2 genotypes were determined by real-time polymerase chain reaction (RT-PCR), and TIMP-2 genotypes were identified using a PCR-restriction fragment length polymorphism (RFLP) method in 210 breast cancer patients and 250 frequency-matched control women. Association of the clinicopathological parameters and the genetic markers with risk of breast cancer was assessed using univariate analyses. We found that the variant MMP-2 genotype (−1306CT or TT) was associated with substantially reduced risk of breast cancer [odds ratio (OR), 0.49; 95 % confidence interval (95 % CI), 0.033–0.73], compared with the CC genotype. For TIMP-2, a moderately reduced risk of the cancer (OR, 0.57; 95 % CI, 0.37–0.87) was also associated with the variant allele (−418GC or CC), compared with the GG common allele. Furthermore, polymorphisms in both genes seem to have additive effects and the highest risk for breast cancer has been observed in those with MMP-2 CC genotype and TIMP-2 GC or CC genotype (p = 0.006). A significant association was also found between the CC genotype and the aggressive forms of breast cancer as defined by advanced stages at the time of diagnosis and metastasis. This is the first report on the association of MMP-2 and TIMP-2 gene polymorphisms in breast cancer in Tunisian population. Our results suggest that the presence of the variant allele in the promoter of MMP-2 or TIMP-2 may be a protective factor for the development of breast cancer.
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References
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.
Kestler DP, Foster JS, Bruker CT, et al. ODAM expression inhibits human breast cancer tumorigenesis. Breast Cancer (Auckl). 2011;5:73–85.
Chouchane L, Boussen H, Sastry KS. Breast cancer in Arab populations: molecular characteristics and disease management implications. Lancet Oncol. 2013;14:e417–24.
Yadav L, Puri N, Rastogi V, Satpute P, Ahmad R, Kaur G. Matrix metalloproteinases and cancer—roles in threat and therapy. Asian Pac J Cancer Prev. 2014;15(3):1085–91.
Radisky ES, Radisky DC. Matrix metalloproteinase-induced epithelial-mesenchymal transition in breast cancer. J Mammary Gland Biol Neoplasia. 2010;15:201–12.
Price SJ, Greaves DR, Watkins H. Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: role of Sp1 in allele-specific transcriptional regulation. J Biol Chem. 2001;276:7549–58.
Hajitou A, Sounni NE, Devy L, et al. Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2: effect on in vivo mammary tumor growth and angiogenesis. Cancer Res. 2001;61:3450–7.
Ross JS, Kaur P, Sheehan CE, Fisher HA, Kaufman Jr RA, Kallakury BV. Prognostic significance of matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expression in prostate cancer. Mod Pathol. 2003;16:198–205.
Lambert E, Dasse E, Haye B, Petitfrere E. TIMPs as multifacial proteins. Crit Rev Oncol Hematol. 2004;49:187–98.
Hirano K, Sakamoto T, Uchida Y, et al. Tissue inhibitor of metalloproteinases-2 gene polymorphisms in chronic obstructive pulmonary disease. Eur Respir J. 2001;18:748–52.
Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci. 1977;74(12):5463–7.
Saeeed HM, Alanazi MS, Alshahrani O, Parine NR, Alabdulkarim HA, Shalaby MA. Matrix metalloproteinase-2 C(-1306)T promoter polymorphism and breast cancer risk in the Saudi population. Acta Biochim Pol. 2013;60:405–9.
Delgado-Encixso I, Cepeda-Lopez FR, Monrroy-Guizar EA, et al. Matrix metalloproteinase-2 promoter polymorphism is associated with breast cancer in a Mexican population. Gynecol Obstet Investig. 2008;65:68–72.
Zhou Y, You C, Miao X, et al. 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. Carcinogenesis. 2004;25:399–404.
Raoehe AV, Frazzon AP, Agnes G, Damin AP, Hartman AA, Graudenz MS. Detection of polymorphisms in the promoter of matrix metalloproteinase 2 and 9 genes in breast cancer in South Brazil: preliminary results. Breast Cancer Res Treat. 2007;102:123–4.
Lei H, Hemminki K, Altieri A, et al. Promoter polymorphism in matrix metalloproteinases and their inhibitors: few associations with breast cancer susceptibility and progression. Breast Cancer Res Treat. 2007;103:61–9.
Beeghly-Fadiel A, Lu W, Long JR, et al. Matrix metalloproteinase-2 polymorphisms and breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev. 2009;18:1770–6.
Saeed HM, Alanazi MS, Parine NR, et al. Matrix metalloproteinase-2 (-1306C > T) promoter polymorphism and risk of colorectal cancer in the Saudi population. Asian Pac J Cancer Prev. 2013;14:6025–30.
Xiaoping M, Chunyuan Y, Wen T, Ping X, Gang L, Wenfu L, et al. A functional polymorphism in the matrix metalloproteinase-2 gene promoter (-1306C/T) is associated with risk of development but not metastasis of gastric cardia adenocarcinoma. Cancer Res. 2003;63:3987–90.
Yifeng Z, Chunyuan Y, Xiaoping M, Wen T, Gang L, Ping X, et al. 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. Carcinogenesis. 2004;25:399–404.
Chunyuan Y, Kaifeng P, Deyin X, Gang L, Wen T, Lian Z, et al. Correlation between a single nucleotide polymorphism in the matrix metalloproteinase-2 promoter and risk of lung cancer. Cancer Res. 2002;62:6430–3.
Chunyuan Y, Yifeng Z, Xiaoping M, Ping X, Wen T, Dongxin L. Functional haplotypes in the promoter of matrix metalloproteinase-2 predict risk of the occurrence and metastasis of esophageal cancer. Cancer Res. 2004;64:7622–8.
Hirano K, Sakamoto T, Uchida Y, Morishima Y, Masuyama K, Ishii Y, et al. Tissue inhibitor of metalloproteinases-2 gene polymorphisms in chronic obstructive pulmonary disease. Eur Respir J. 2001;18:748–52.
Jiang Y, Goldberg ID, Shi YE. Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene. 2002;21:2245–52.
Zhang M, Teng XD, Guo XX, Li ZG, Han JG, Yao L. Expression of tissue levels of matrix metalloproteinases and their inhibitors in breast cancer. Breast. 2013;22:330–4.
Wu CY, Wu MS, Chen CJ, et al. Clinicopathological significance of MMP2 and TIMP2 genotypes in gastric cancer. Eur J Cancer. 2007;43:799–808.
Zagouri F, Sergentanis TN, Gazouli M, et al. MMP-2–1306 C > T polymorphism in breast cancer: a case-control study in a South European population. Mol Biol Rep. 2013;40:5035–40.
Slattery ML, John E, Torres-Mejia G, et al. Matrix metalloproteinase genes are associated with breast cancer risk and survival: the Breast Cancer Health Disparities Study. PLoS One. 2013;8:63–5.
Talvensaari-Mattila A, Paakko P, Turpeenniemi-Hujanen T. Matrix metalloproteinase-2 (MMP-2) is associated with survival in breast carcinoma. Br J Cancer. 2003;89:1270–5.
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Ben Néjima, D., Ben Zarkouna, Y., Gammoudi, A. et al. Prognostic impact of polymorphism of matrix metalloproteinase-2 and metalloproteinase tissue inhibitor-2 promoters in breast cancer in Tunisia: case-control study. Tumor Biol. 36, 3815–3822 (2015). https://doi.org/10.1007/s13277-014-3023-5
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DOI: https://doi.org/10.1007/s13277-014-3023-5