Abstract
BackgroundTIMP-2 gene plays an important role in the development of breast cancer. The present study was conducted to evaluate whether TIMP-2 gene polymorphisms are associated with breast cancer risk in a Han Chinese cohort.MethodsSix single nucleotide polymorphisms (SNPs) within the TIMP-2 gene in 571 breast cancer and 578 healthy control subjects were genotyped through the Agena MassARRAY. Logistic regression analysis was used to assess the influence of TIMP-2 polymorphisms on breast cancer. Functional annotation of TIMP-2 variants and TIMP-2 expression were analyzed by bioinformatics.ResultsBioinformatics analysis found that rs4789936 was likely to affect transcription factor binding, motifs, DNase footprint, and DNase peaks; and TIMP-2 was under-expressed in breast cancer, the risk allele of rs4789936 was associated with increased expression of TIMP-2 in peripheral blood samples. Importantly, individuals carrying TIMP-2 rs2277698 T allele have a 19% lower risk of breast cancer than individuals with allele C, providing protection (OR = 0.81, 95%CI = 0.67–0.99, p = 0.041). In the breast cancer patients with c-erb positive and PR positive, when the CC genotype was used as a reference, individuals carrying the TT genotype increased the risk of breast cancer. Haplotype analysis showed “TCC” was associated with a reduced risk of breast cancer (OR = 0.79, 95%CI = 0.63–0.97, p = 0.028).ConclusionOur study indicated that TIMP-2 rs2277698 was associated with breast cancer susceptibility.
Highlights
Tissue inhibitor of metalloproteinase-2 (TIMP-2) gene plays an important role in the development of breast cancer
The correlation between the genetic variants of TIMP-2 and susceptibility to stroke [13], oral squamous cell carcinoma [8], prostate cancer [9], abdominal aortic aneurysm [10], head and neck squamous cell carcinoma [11], and gastric cancer [12] have been identified in a number of studies worldwide. These findings suggest that evaluation of TIMP-2 polymorphism in cancers may be useful as a prognostic indicator
Examination of 1097 breast cancer tissues and 114 normal tissues from The Cancer Genome Atlas (TCGA) using the UALCAN database demonstrated that TIMP-2 was under-expressed in breast cancer tissues (Fig. 2a)
Summary
TIMP-2 gene plays an important role in the development of breast cancer. The present study was conducted to evaluate whether TIMP-2 gene polymorphisms are associated with breast cancer risk in a Han Chinese cohort. Domestic and foreign scholars believe that extracellular matrix (ECM) plays a vital role in the invasion and migration of breast cancer cells [2]. These studies have demonstrated that degradation of the basement membrane ECM is critical for the progression of tumorigenesis and metastasis [3]. Genetic polymorphisms in the TIMP-2 gene, located on chromosome 17q25, may lead to an increase or decrease in TIMP-2 activity and subsequently disrupt the balance between the activity of TIMP-2 and MMP-2 This disrupted balance could influence cancer development and progression [7].
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