Synergistic effect of collagenase-1 (MMP1), stromelysin-1 (MMP3) and gelatinase-B (MMP9) gene polymorphisms in breast cancer

Abstract

BackgroundExtracellular matrix degradation by matrix metalloproteinases (MMPs) is an important mechanism involved in tumor invasion and metastasis. Genetic variations of MMPs have shown association with multiple cancers. The present study is focused to elucidate the association of MMP-1, 3 and 9 genetic variants with respect to epidemiological and clinicopathological variables by haplotype, LD, MDR, survival in silico analyses among South Indian women.Material and methodsMMP3–1171 5A/6A and MMP9–1562 C/T SNPs were genotyped by Allele specific polymerase chain reaction and MMP1-1607 1G/2G polymorphism by restriction fragment length polymorphism assays respectively, in 300 BC patients and age-matched 300 healthy controls. Statistical analysis was performed using the SNPStats and SPSS software. Linkage disequilibrium and gene-gene interactions were performed using Haploview and MDR software respectively. Further, transcription factor binding sites in the promoter regions of SNPs under study were carried out using AliBaba2.1 software.ResultsWe have observed an increased frequency of 2G-allele of MMP1, 6A-allele of MMP3 and T-allele of MMP9 (p<0.05) respectively in BC subjects. The 2G-6A haplotype (minor alleles of MMP-1 and MMP-3 respectively) has shown an increased susceptibility to BC. Further, MMP polymorphisms were associated with the clinical characteristics of BC patients such as steroid hormone receptor status, lymph node involvement and metastasis. SNP combinations were in perfect LD in controls. MDR analysis revealed a positive interaction between the SNPs. 5-years survival rate and cox-regression analysis showed a significant association with clinicopathological variables.ConclusionOur results suggest that MMP1–1607 1G/2G, MMP3–1171 5A/6A and MMP9–1562 C/T gene polymorphisms have synergistic effect on breast cancer. The interactions of MMPs clinical risk factors such as lymph node involvement has shown a strong correlation and might influence the 5-years survival rate, suggesting their potential role in the breast carcinogenesis.

Association of matrix metalloproteinases 3 and 9 single nucleotide polymorphisms with breast cancer risk: A case‑control study

“…These results are in line with previous findings of AbdRaboh in 2016, who reported that 5A allele is associated with increased risk of BC in a sample of BC patients in UAE (23). In addition, Padala in 2017, reported that 5A/6A genotype increased the risk of BC development among Indian population (22).…”

“…Furthermore, and along with investigating the variations in gene expression, SNPs analysis may be promising predictive and prognostic markers, which may lead to better management of the disease (18). Most of the reported SNPs in MMPs genes are functionally implicated in the progression of BC (19)(20)(21) particularly; those found in the promoter region and alter gene expression, which may result in imbalance in the MMP system, which, in turn, leads to excessive degradation of ECM and deregulation of ECM dynamics in cancer development (22).…”

<p>Matrilysins and Stromelysins in Pathogenesis and Diagnostics of Cancers</p>

“…5A/6A MMP-3 polymorphism was found to be significantly connected with lymph node metastases, which have influence to the survival rate of patients. 70 …”

FOXN3 is downregulated in osteosarcoma and transcriptionally regulates SIRT6, and suppresses migration and invasion in osteosarcoma

“…FOXN3 suppresses MMP-9 secretion via the regulation of SIRT6 expression. MMP-9 can digest gelatins or denatured collagens (24), and has been reported to promote metastasis in some types of cancers (25,26). In addition, SIRT6 was proposed to regulate MMP-9 expression in OS and non-small cell lung cancer (27).…”