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TIMP-2 gene rs4789936 polymorphism is associated with increased risk of breast cancer and poor prognosis in Southern Chinese women.

ABSTRACT: Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an endogenous inhibitor of matrix metalloproteinase-2, and an important regulator of cancer growth and metastasis. Here, we evaluated the relationship between TIMP-2 gene rs4789936 polymorphism and breast cancer risk and prognosis in Southern Chinese women. Analysis of 480 breast cancer cases and 530 healthy controls revealed that compared to the CC genotype, the TT/CT genotypes increased the risk of breast cancer (CT: odds ratio (OR)=1.46, 95%CI: 1.11-1.92; TT: OR=2.57, 95%CI: 1.76-3.77). Stratified and cross-over analyses indicated that the increased risk of the rs4789936 polymorphism was associated with age, smoking, drinking, and the body mass index. The TT and CT genotypes were more common than the CC genotype in patients with lymph node metastases (TT: OR=2.54, 95%CI: 1.54-4.18; CT: OR=2.10, 95%CI: 1.40-3.15), advanced stage (TT: OR=1.91, 95%CI: 1.17-3.14; CT: OR=1.80, 95%CI: 1.20-2.70), or progesterone receptor positive cancer (TT: OR=2.02, 95%CI: 1.23-3.32). Multivariate cox regression indicated the CT and TT genotypes (HR=4.65, 95%CI: 1.26-17.18, P=0.021; HR=6.62, 95%CI: 1.51-29.11, P=0.012) were associated with poor prognosis in breast cancer patients. Thus, the TIMP-2 gene rs4789936 polymorphism is associated with elevated breast cancer risk and may be an independent prognosis factor in breast cancer patients.

SUBMITTER: Liu G

PROVIDER: S-EPMC7732285 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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TIMP-2 gene rs4789936 polymorphism is associated with increased risk of breast cancer and poor prognosis in Southern Chinese women.

Liu Gaoming G Luo Jiayou J

Aging 20201007 19

Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an endogenous inhibitor of matrix metalloproteinase-2, and an important regulator of cancer growth and metastasis. Here, we evaluated the relationship between TIMP-2 gene rs4789936 polymorphism and breast cancer risk and prognosis in Southern Chinese women. Analysis of 480 breast cancer cases and 530 healthy controls revealed that compared to the CC genotype, the TT/CT genotypes increased the risk of breast cancer (CT: odds ratio (OR)=1.46, 95% ...[more]

PMID: 33027062

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Project description:BackgroundTissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional protein that can directly regulate apoptosis and metastasis. In this study, we investigated the functional and molecular mechanisms by which TIMP-1 influences triple-negative breast cancer (TNBC).MethodsThe expression level of TIMP-1 in breast cancer tissues was analyzed using the ONCOMINE microarray database. The overall survival of patients with distinct molecular subtypes of breast cancer stratified by TIMP-1 expression levels was evaluated using Kaplan-Meier analysis. Bisulfate sequencing PCR (BSP) was used to analyze the methylation status of the TIMP-1 promoter. Real-time-PCR (RT-PCR), Western blot and ELISA assays were used to evaluate gene and protein expression in cell lines and human tissue specimens. In addition, TIMP-1 function was analyzed using a series of in vitro and in vivo assays with cells in which TIMP-1 was inhibited using RNAi or neutralizing antibodies.ResultsWe found that serum TIMP-1 levels were strongly enhanced in patients with TNBC and that elevated TIMP-1 levels were associated with a poor prognosis in TNBC. However, TIMP-1 levels were not significantly associated with overall survival in other subtypes of breast cancer or in the overall population of breast cancer patients. We also report the first evidence that the TIMP-1 promoter is hypomethylated in TNBC cell lines compared with non-TNBC cell lines, suggesting that aberrant TIMP-1 expression in TNBC results from reduced DNA methylation. RNAi-mediated silencing of TIMP-1 in TNBC cells induced cell cycle arrest at the G1 phase and reduced cyclin D1 expression. In addition, mechanistic analyses revealed that the p-Akt and p-NF-κB signaling pathways, but not the GSK-3β and MAPK1/2 pathways, are associated with TIMP-1 overexpression in TNBC cells. Moreover, neutralizing antibodies against TIMP-1 significantly decreased the rate of tumor growth in vivo.ConclusionsOur findings suggest that TIMP-1 is a biomarker indicative of a poor prognosis in TNBC patients and that targeting TIMP-1 may provide an attractive therapeutic intervention specifically for triple-negative breast cancer patients.

Project description:Breast cancer is one of the most widespread malignancies in females, and the incidence rate has been increasing in recent years in the world. Genetic factors play an important role in the occurrence of breast cancer. Our study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) of claudin 10 (CLDN10) (rs1325774, rs7333503, rs3751334) and breast cancer and the clinical characteristics of patients.A total of 104 patients with breast cancer and 118 healthy controls were recruited in our study between 2013 and 2015. The SNPscan system was used for genotyping. Demographic information, health status, anthropometric parameters and clinical data were considered in analysis. Statistical analysis of the data was carried out using the Student t test, the Chi-square test (X2) or Fisher exact test and unconditional logistic regression analysis. The Gene Expression Profiling Interactive Analyses application (GEPIA) was used to analysis the expression of CLDN10 in breast cancer tissues and normal samples.The polymorphism of rs1325774 was significantly associated with an increased risk of breast cancer (T/G vs T/T: OR = 2.073, 95% CI = 1.095-3.927, P = .025). After adjusting for age, the association remained statically significant (T/G vs T/T: OR = 2.067, 95% CI = 1.070-3.867, P = .026). Furthermore, harbouring G allele in rs1325774 position was significantly associated with increased risk of breast cancer (OR = 1.993, 95% CI = 1.107-3.589, P = .022). However, no significant association among rs7333503, rs3751334, and breast cancer. The expression level of CLDN10 was reduced in breast cancer tissues compared with normal breast tissues according to the analysis of The Cancer Genome Atlas (TCGA) data through GEPIA.Our results suggest that the polymorphism of rs1325774 associate with increase the breast cancer risk. No significant relationship between rs1325774 polymorphism and clinical as well as pathological characteristics in patients.

Dataset Information

TIMP-2 gene rs4789936 polymorphism is associated with increased risk of breast cancer and poor prognosis in Southern Chinese women.

Publications

TIMP-2 gene rs4789936 polymorphism is associated with increased risk of breast cancer and poor prognosis in Southern Chinese women.

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