title: Prognostic impact of polymorphism of matrix metalloproteinase-2 and metalloproteinase tissue inhibitor-2 promoters in breast cancer in Tunisia: case-control study.
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.
authors: Unité de Biochimie et de Biologie Moléculaire 02/UR/09-04, Faculté des Sciences de Tunis, Tunis, Tunisia, dalelbennejima@yahoo.com.
authors: Dalel
authors: D
authors: Ben Néjima
authors: Yosr
authors: Y
authors: Ben Zarkouna
authors: Amor
authors: A
authors: Gammoudi
authors: Mohamed
authors: M
authors: Manai
authors: Hamouda
authors: H
authors: Boussen
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*
chemical_list: D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2
references: J Biol Chem. 2001 Mar 9;276(10):7549-58
references: 11114309
references: Eur Respir J. 2001 Nov;18(5):748-52
references: 11757622
references: Acta Biochim Pol. 2013;60(3):405-9
references: 24051440
references: Breast Cancer Res Treat. 2007 May;103(1):61-9
references: 17033924
references: Cancer Res. 2002 Nov 15;62(22):6430-3
references: 12438229
references: Cancer Epidemiol Biomarkers Prev. 2009 Jun;18(6):1770-6
references: 19454611
references: PLoS One. 2013 May 16;8(5):e63165
references: 23696797
references: Eur J Cancer. 2007 Mar;43(4):799-808
references: 17236757
references: Cancer Res. 2004 Oct 15;64(20):7622-8
references: 15492291
references: Breast Cancer (Auckl). 2011;5:73-85
references: 21603257
references: Asian Pac J Cancer Prev. 2013;14(10):6025-30
references: 24289619
references: Br J Cancer. 2003 Oct 6;89(7):1270-5
references: 14520459
references: Mol Biol Rep. 2013 Aug;40(8):5035-40
references: 23661021
references: Mod Pathol. 2003 Mar;16(3):198-205
references: 12640098
references: Oncogene. 2002 Mar 28;21(14):2245-52
references: 11948407
references: Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463-7
references: 271968
references: J Mammary Gland Biol Neoplasia. 2010 Jun;15(2):201-12
references: 20440544
references: Lancet Oncol. 2013 Sep;14(10):e417-24
references: 23993386
references: Crit Rev Oncol Hematol. 2004 Mar;49(3):187-98
references: 15036259
references: Carcinogenesis. 2004 Mar;25(3):399-404
references: 14604886
references: Int J Cancer. 2010 Dec 15;127(12):2893-917
references: 21351269
references: Gynecol Obstet Invest. 2008;65(1):68-72
references: 17851253
references: Breast. 2013 Jun;22(3):330-4
references: 22995648
references: Breast Cancer Res Treat. 2007 Mar;102(1):123-4
references: 17260100
references: Cancer Res. 2003 Jul 15;63(14):3987-90
references: 12873995
references: Asian Pac J Cancer Prev. 2014;15(3):1085-91
references: 24606423
references: Cancer Res. 2001 Apr 15;61(8):3450-7
references: 11309307