Role of Endothelial Nitric Oxide Synthase in Breast Cancer

Breast cancer (BC) is the most common form of carcinoma and a primary cause of morbidity and mortality globally. Oxidative stress represents as an important factor in carcinogenesis and may play a role in initiation and progression of tumors. Oxidative stress–induced NO• damage to DNA includes a multitude of lesions, many of which are mutagenic and have multiple roles in cancer and aging. It is caused by an unfavorable balance between reactive oxygen species/reactive nitrogen species (ROS/RNS) and antioxidant defenses. ROS/RNS are generated during normal cellular metabolism, as a result of the influence of various environmental factors, as well as during pathological processes. Nitric oxide (NO•) is a ubiquitous, short-lived free radical produced from L-arginine by nitric oxide synthases (NOSs), and isoforms of NOS exist, depending on the site of origin: endothelial (eNOS), neuronal (nNOS), mitochondrial (mtNOS), and inducible (iNOS). eNOS is responsible for the endothelial synthesis of NO• and has shown to modulate cancer-related events such as inflammation, angiogenesis, apoptosis, cell cycle, invasion, and metastasis. Genetic studies also showed that eNOS gene polymorphisms are associated with the development of breast cancer. Therefore, selective targeting of eNOS may prove a potential strategy for prevention and treatment of breast cancer

Association of the MMP1–1607 1G>2G, MMP3-1171 5A>6A and MMP9-1562 C>T genotypes with breast cancer susceptibility and clinicopathological characteristics.

<p>Association of the MMP1–1607 1G>2G, MMP3-1171 5A>6A and MMP9-1562 C>T genotypes with breast cancer susceptibility and clinicopathological characteristics.</p

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

<div><p>Background</p><p>Extracellular 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.</p><p>Material and methods</p><p>MMP3–1171 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.</p><p>Results</p><p>We 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.</p><p>Conclusion</p><p>Our 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.</p></div

Interaction dendrogram of SNP-SNP by MDR analysis.

<p>Interaction dendrogram of SNP-SNP by MDR analysis.</p

Clinicopathological parameters among the breast cancer patients.

<p>Clinicopathological parameters among the breast cancer patients.</p

Genotype and allele frequencies distribution for MMP-1, MMP-3 and MMP-9 gene polymorphisms in controls and breast cancer subjects.

<p>Genotype and allele frequencies distribution for MMP-1, MMP-3 and MMP-9 gene polymorphisms in controls and breast cancer subjects.</p

Forward and reverse primers and PCR conditions for genotyping of selected polymorphic variants of MMP-1,-3 & -9 genes.

<p>Forward and reverse primers and PCR conditions for genotyping of selected polymorphic variants of MMP-1,-3 & -9 genes.</p

Effect of the MMP-1, -3 & -9 polymorphisms on transcription factor binding sites.

<p>Effect of the MMP-1, -3 & -9 polymorphisms on transcription factor binding sites.</p

Pairwise linkage disequilibrium estimates in controls and cases group.

<p>Pairwise linkage disequilibrium estimates in controls and cases group.</p