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

Fine mapping and sequence analysis reveal a promising candidate gene encoding a novel NB-ARC domain derived from wild rice (Oryza officinalis) that confers bacterial blight resistance

Bacterial blight disease of rice caused by Xanthomonas oryzae pv. oryzae (Xoo) is one of the most serious constraints in rice production. The most sustainable strategy to combat the disease is the deployment of host plant resistance. Earlier, we identified an introgression line, IR 75084-15-3-B-B, derived from Oryza officinalis possessing broad-spectrum resistance against Xoo. In order to understand the inheritance of resistance in the O. officinalis accession and identify genomic region(s) associated with resistance, a recombinant inbred line (RIL) mapping population was developed from the cross Samba Mahsuri (susceptible to bacterial blight) × IR 75084-15-3-B-B (resistant to bacterial blight). The F2 population derived from the cross segregated in a phenotypic ratio of 3: 1 (resistant susceptible) implying that resistance in IR 75084-15-3-B-B is controlled by a single dominant gene/quantitative trait locus (QTL). In the F7 generation, a set of 47 homozygous resistant lines and 47 homozygous susceptible lines was used to study the association between phenotypic data obtained through screening with Xoo and genotypic data obtained through analysis of 7K rice single-nucleotide polymorphism (SNP) chip. Through composite interval mapping, a major locus was detected in the midst of two flanking SNP markers, viz., Chr11.27817978 and Chr11.27994133, on chromosome 11L with a logarithm of the odds (LOD) score of 10.21 and 35.93% of phenotypic variation, and the locus has been named Xa48t. In silico search in the genomic region between the two markers flanking Xa48t identified 10 putatively expressed genes located in the region of interest. The quantitative expression and DNA sequence analysis of these genes from contrasting parents identified the Os11g0687900 encoding an NB-ARC domain-containing protein as the most promising gene associated with resistance. Interestingly, a 16-bp insertion was noticed in the untranslated region (UTR) of the gene in the resistant parent, IR 75084-15-3-B-B, which was absent in Samba Mahsuri. The association of Os11g0687900 with resistance phenotype was further established by sequence-based DNA marker analysis in the RIL population. A co-segregating PCR-based INDEL marker, Marker_Xa48, has been developed for use in the marker-assisted breeding of Xa48t

Genomic diversity of the Muslim population from Telangana (India) inferred from 23 autosomal STRs

Aim This study aimed to investigate the genomic diversity and population structure in the Muslim community of Telangana, India, using 23 autosomal microsatellite genetic markers. We also examined genetic relatedness between Muslim and non-Muslim populations of India. Subjects and methods A sample of 184 randomly selected unrelated healthy Muslim individuals from the Telangana state were included in this study. The genotyping of 23 autosomal STR markers included in PowerPlex® Fusion 6 C multiplex system (Promega)was done. Results A total of 273 alleles were observed in the studied population, and locus SE33 showed 37 observed alleles, which is the highest number of observed alleles among all the studied loci. Among all the studied loci the most polymorphic and discriminatory locus was SE33, with the values of polymorphic information content (PIC) = 9.411E–01 and power of discrimination (PD) = 9.865E–01. Observed heterozygosity ranged from 6.630E–01 (D22S1045) to 9.239E–01 (SE33). Discrimination power, exclusion power, matching probability and paternity index for all the studied loci were 1.00E + 00, 1.00E + 00, 2.01E–28, and 5.68E + 09, respectively. The studied Muslim population showed genetic relatedness with non-Muslim populations i.e. populations of central India, Jharkhand, and Uttar Pradesh, suggesting the conversion of Hindus during the Muslim invasion. Conclusion Neighbor-joining (NJ) tree and principal component analysis (PCA) revealed that the studied population showed genetic affinity with communities of Jharkhand, Madhya Pradesh and Uttar Pradesh states. The genetic data of this study may be useful for forensic, medical, and anthropological studies

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

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

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