Association of superoxide dismutases and NAD(P)H quinone oxidoreductases with prognosis of patients with breast carcinomas

Abstract

Associations of transcript levels of oxidative stress-modifying genes SOD2, SOD3, NQO1 and NQO2 and their functional single nucleotide polymorphisms (SNPs) rs4880, rs1799895, rs2536512, rs699473, rs1800566 and rs1143684 with prognosis of breast cancer patients were studied. SNPs were assessed by allelic discrimination in a cohort of 321 breast cancer patients from the Czech Republic. Transcript levels were determined by real-time polymerase chain reaction (PCR) with absolute quantification in tumor and adjacent non-neoplastic control tissues. Both genotypes and transcript levels were then compared with available clinical data on patients. Patients carrying low activity allele Leu in NQO2 rs1143684 had a greater incidence of stage 0 or I disease (i.e., better prognosis) than patients with the Phe/Phe genotype. This association was more evident in patients without expression of progesterone receptors (p 5 0.031). Patients carrying the Thr allele in SOD3 rs2536512 SNP had a significantly greater incidence of tumors expressing estrogen receptors than patients carrying the Ala/Ala genotype (p 5 0.007). SOD3 transcript level was significantly higher in grade 1 or 2 tumors than in grade 3 tumors (p 5 0.006). Patients carrying T allele in SOD3 rs699473 SNP had significantly poorer progression-free survival (PFS) than patients carrying the CC genotype (p 5 0.038). The same applied to the subgroup of patients treated by hormonal regimens (p 5 0.021). Patients carrying the high activity Ala/Ala genotype in SOD2 (rs4880) had significantly poorer PFS than Val allele carriers in the group treated by cyclophosphamide but not hormonal regimens (p 5 0.004). Our results suggest that NQO2, SOD2 and SOD3 may significantly modify prognosis of breast cancer patients and that their significance should be further characterized.Breast cancer is the most common cancer in women. In 2008, about 1,383,523 new cases of invasive breast cancer were diagnosed worldwide. 1 The necessity of treating such a large number of patients calls for efficient tools that can be used for subgrouping patients according to estimated prognosis. A different spectrum of treatment modalities with diverse mechanisms of action and adverse effects could then be offered to various prognostic groups. Besides well-established classical prognostic factors such as tumor size, nodal status, grading and expression of hormonal receptors, numerous biological molecules are under investigation as potential prognostic biomarkers in breast carcinomas.Excess of oxidative stress, mediated by reactive oxygen species, may cause cellular deregulation leading to cell apoptosis, 2 proliferation or tumor promotion. 3 Alkylation and topoisomerase poisoning present the major mechanisms of action of cyclophosphamide and anthracyclines, respectively. Oxidative stress represents an additional cytotoxic mechanism. 4,5 One of the initial molecules of oxidative stress, superoxide anion radical, is formed by the univalent reduction of triplet-state molecular oxygen. This process is mediated by e...

There is no relationship between SOD2 Val-16Ala polymorphism and breast cancer risk or survival

“…By reading the full texts, 11 studies were out of scope as they did not satisfy the inclusion criteria (one meeting abstract, three animal experiments or cell cultures and seven without available data). Finally, a total of 34 publications were available for the present meta-analysis, 26 for risk analysis and eight for survival analysis (58)(59)(60)(61)(62)(63)(64)(65). The flow chart of study search and inclusion was demonstrated in Fig.…”

Extracellular superoxide dismutase and its role in cancer

“…Concurrently, in a normal mammary epithelial cell line, siRNA-mediated knockdown of EcSOD promoted clonogenic capacity, tumorsphere formation, and wound healing in MCF10A cells [117]. In addition to the Oncomine analysis showing a prominent down-regulation of EcSOD expression in breast carcinomas, an inverse correlation between the mRNA expression levels of EcSOD and breast cancer stage has been reported [116 118]. Immunohistochemistry data also show a significant decrease in EcSOD protein expression in both ductal carcinoma in situ and invasive breast carcinoma compared to normal tissue [116], further suggesting that loss of EcSOD provides a selective advantage in cancer cells.…”

Transcript expression and genetic variability analysis of caspases in breast carcinomas suggests CASP9 as the most interesting target

“…Blood samples from 615 patients for the genotyping validation study were collected from patients treated in The Faculty Hospital Motol, Institute for the Care for Mother and Child, The Fac ulty Hospital Kralovske Vinohrady (Prague, Czech Republic), and The Hospital Atlas (Zlin, Czech Republic). The processing of the tissue and blood samples was described in detail previously [10,18]. Histologi cal classification of carcinomas was performed according to standard diagnostic procedures [19].…”