title: Association of matrix metalloproteinase-8 gene variation with breast cancer prognosis.
abstract: Animal and cell studies indicate an inhibitory effect of matrix metalloproteinase-8 (MMP8) on tumorigenesis and metastasis. We investigated whether MMP8 gene variation was associated with breast cancer metastasis and prognosis in humans. We first studied nine tagging single nucleotide polymorphisms (SNP) in the MMP8 gene in 140 clinically and pathologically well-characterized breast cancer patients. Four of the SNPs were found to be associated with lymph node metastasis, the most pronounced being a promoter SNP (rs11225395) with its minor allele (T) associating with reduced susceptibility to lymph node metastasis (P = 0.02). This SNP was further evaluated for association with cancer relapse and survival among a cohort of approximately 1,100 breast cancer patients who had been followed for cancer recurrence and mortality for a median of 7.1 years. The T allele was associated with reduced cancer relapse and greater survival, particularly among patients with earlier stage cancer. Among patients of tumor-node-metastasis stage 0 to II, the adjusted hazard ratio of disease-free survival was 0.7 [95% confidence interval (95% CI), 0.5-0.9] for patients carrying T allele compared with those homozygous for the C allele (P = 0.02). In vitro experiments showed that the T allele had higher promoter activity than the C allele in breast cancer cells. Electrophoretic mobility shift assays showed binding of nuclear proteins to the DNA sequence at the SNP site of the T allele but not that of the C allele. The data suggest that MMP8 gene variation may influence breast cancer prognosis and support the notion that MMP8 has an inhibitory effect on cancer metastasis.
authors.affiliation: Laboratory for Experimental Oncology, Department of General Medical Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Decock
authors.forename: Ji-Rong
authors.initials: JR
authors.lastname: Long
authors.forename: Ross C
authors.initials: RC
authors.lastname: Laxton
authors.forename: Xiao-Ou
authors.initials: XO
authors.lastname: Shu
authors.forename: Conrad
authors.initials: C
authors.lastname: Hodgkinson
authors.forename: Wouter
authors.initials: W
authors.lastname: Hendrickx
authors.forename: Eve G
authors.initials: EG
authors.lastname: Pearce
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Gao
authors.forename: Andresa C
authors.initials: AC
authors.lastname: Pereira
authors.forename: Robert
authors.initials: R
authors.lastname: Paridaens
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Shu
authors.initials: S
authors.lastname: Ye
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006239:Haplotypes; D006801:Humans; D008207:Lymphatic Metastasis; D020784:Matrix Metalloproteinase 8 / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis
chemical_list: D020784:Matrix Metalloproteinase 8