Manganese superoxide dismutase in breast cancer: From molecular mechanisms of gene regulation to biological and clinical significance (original) (raw)
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Two polymorphic variants of manganese superoxide dismutase (MnSOD), with either Ile or Thr at amino acid 58, (Ile 58 MnSOD or Thr 58 MnSOD), have been found in the human population. The MnSOD activity of these two variants and their effects on the malignant phenotype of human breast cancer MCF-7 cells were compared. It was demonstrated that MnSOD-overexpressing clones obtained from transfection of the two MnSOD cDNAs into MCF-7 cells had increased MnSOD immunoreactive protein and increased MnSOD activity. Cells overexpressing Ile 58 MnSOD had 3-fold higher MnSOD activity than cells overexpressing Thr 58 MnSOD in vivo at an equal MnSOD protein level. Tumor-suppressive effects of MnSOD-overexpressing cells were indicated by: (a) decreased plating efficiency; (b) elongated cell population doubling time; (c) lower clonogenic fraction in soft agar; and (d) complete inhibition or delayed onset of tumor formation in nude mice.
Journal of Biomedicine and Biotechnology, 2004
Manganese superoxide dismutase (Mn-SOD), localized at the mitochondrial matrix, has the ability to protect cells against oxidative damage. It has been reported that low levels of Mn-SOD gene expression cause the development of certain kind of tumors. On the other hand, overexpression of Mn-SOD gene may play an important role in the development of cancer. In our study, we find that Mn-SOD activity was higher in nonaggressive (MCF-7) and aggressive (BT-549 and 11-9-14) breast cancer cell lines compared to that of nontumorigenic (MCF-12A and MCF-12F) mammary epithelial cell lines. We also observed an increased expression of Mn-SOD gene in cancerous cell lines. The elevated level of SOD activity in nonaggressive and aggressive breast epithelial cell lines was associated with some changes in nucleotide sequence.
Journal of breast cancer, 2012
Although the etiology of breast cancer is multifactorial, oxidative stress plays an important role in carcinogenesis. In this study, manganese superoxide dismutase (MnSOD) gene polymorphism and activity were evaluated in benign and breast cancer tissue. One hundred and one females were enrolled in this study, 65 who were histopathologically diagnosed with breast cancer and 46 who were benign patients. MnSOD enzyme activity was determined using an indirect competitive inhibition assay and MnSOD gene polymorphism using poly merase chain reaction and agarose gel electrophoresis. MnSOD enzymatic activity (79.83±42.14) was lower in breast cancer tissue compared to benign tumors (236.18±46.37). At the same time, MnSOD enzymatic activity among Ala/Val patients was significantly lower in breast cancer tissue (39.19±7.33) than in Val/Val malignant breast tumors tissue (96.9±22.9). MnSOD enzymatic activity was significantly lower in Val/Val cancer tissue (96.9±22.9) than in benign tissue (255...
Human manganese superoxide dismutase suppresses HER2/neu-mediated breast cancer malignancy
Febs Letters, 2007
The up-regulation of HER2/neu is associated with human malignancies and is a useful target for developing anticancer drugs. Overexpression of human manganese superoxide dismutase (MnSOD) has been demonstrated to effectively suppress various carcinoma cells, including breast carcinomas, in vitro and in vivo. This study demonstrates that MnSOD effectively suppresses HER2/neu oncogene expression at the transcriptional level. Additionally, stable transfection was
2004
The most important cellular protective mechanisms against oxidative stress are antioxidant enzymes. Their action is based on decomposal of reactive oxygen species (ROS) and their transformation to H 2 O 2. Within the mitochondria manganese superoxide dismutase (MnSOD) affords the major defense against ROS. In this study we investigated tissue sections from 101 breast carcinomas for the immunohistochemical expression of MnSOD protein and these results were assessed in relation to various clinicopathological parameters, in order to clarify the prognostic value of this enzyme. The possible relationship to hormone receptor content, anti-apoptotic protein bcl-2, p53 and cell proliferation was also estimated. High expression levels were observed, as 79/101 (78,2%) cases expressed strong immunoreactivity. In this study MnSOD increased in a direct relationship with tumor grade and is therefore inversely correlated with differentiation (p=0.0004). Furthermore, there was a strong positive correlation between MnSOD expression and p53 protein immunoreactivity (p=0.0029). The prognostic impact of MnSOD expression in determining the risk of recurrence and overall survival with both univariate (long-rang test) and multivariate (Cox regression) methods of analysis was statistically not significant. These results indicate that neoplastic cells in breast carcinomas retain their capability to produce MnSOD and thus protected from the possible cellular damage provoked by reactive oxygen species. In addition, MnSOD content varies according to the degree of differentiation of breast carcinoma.
Antioxidants & Redox Signaling, 2013
Aim: Whereas earlier reports highlighted a tumor suppressor role for MnSOD, recent evidence indicates increased expression in a variety of human cancers including aggressive breast carcinoma. In the present report, we hypothesized that MnSOD expression is significantly amplified in the aggressive breast carcinoma basal subtype and targeting MnSOD could be an attractive strategy for enhancing chemosensitivity of this highly aggressive breast cancer subtype.
Molecular and Cellular Biochemistry, 2010
The manganese superoxide dismutase (MnSOD) ala16val polymorphism has been associated with various diseases including breast cancer. In the present study, we investigated levels of MnSOD protein, enzymatic activity, and mRNA with respect to MnSOD genotype in several human breast carcinoma cell lines and in mouse embryonic fibroblasts (MEF), developed from the MnSOD knockout mouse, stably expressing human MnSOD-ala and MnSODval. In human breast cell lines, the MnSOD-ala allele was associated with increased levels of MnSOD protein and MnSOD protein per unit mRNA. In the MEF transformants, MnSOD activity correlated fairly well with MnSOD protein levels. MnSOD mRNA expression was significantly lower in MnSOD-ala versus MnSOD-val lines. MnSOD protein and activity levels were not related to MnSOD genotype in the transformed MEF, although, as observed in the human breast cell lines, the MEF human MnSOD-ala lines produced significantly more human MnSOD protein per unit mRNA than the human MnSOD-val lines. This suggests that there is more efficient production of MnSOD-ala protein compared to MnSOD-val protein. Examination of several indicators of reactive oxygen species levels, including superoxide and hydrogen peroxide, in wild-type MEF and in MEF expressing similar elevated amounts of MnSOD-ala or val activity did not show differences related to the levels of MnSOD protein expression. In conclusion, in both human breast carcinoma cell lines and MEF cell lines stably transfected with human MnSOD, the MnSOD-ala allele was associated with increased production of MnSOD protein per unit mRNA indicating a possible imbalance in MnSOD protein production from the MnSOD-val mRNA.
Epigenetic Regulation of Manganese Superoxide Dismutase Expression in Human Breast Cancer Cells
Epigenetics, 2006
Malignant breast cancer cells often exhibit lower expression and activity of manganese superoxide dismutase (MnSOD) than their normal cell counterparts; however, the mechanism(s) responsible for this change remains unclear. We examined whether SOD2, the gene encoding MnSOD, was epigenetically repressed in breast cancer cell lines by DNA methylation and histone acetylation. RT-PCR analysis of SOD2 mRNA showed the nontumorigenic breast epithelial cell line MCF-10A to have two to three fold higher expression levels than either UACC-893 or MDA-MB-435 breast carcinoma cells. Analysis of a region in the SOD2 promoter by sodium bisulfite genomic sequencing demonstrated significantly higher levels of CpG methylation in both human breast carcinoma cell lines assessed than in MCF-10A cells. CREB binding in vitro to a cognate site derived from this region was repressed by DNA methylation, and CREB binding to the 5' regulatory region of the SOD2 gene in vivo as determined by ChIP was significantly lower in breast carcinoma cells than in MCF-10A. Increased cytosine methylation was also accompanied by a significant decrease in the level of acetylated histones in the same region of the SOD2 promoter. Finally, a causal link between cytosine methylation and transcriptional repression was established by increasing MnSOD mRNA, protein and activity in breast carcinoma cells using the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine. These findings indicate that epigenetic silencing of SOD2 constitutes one mechanism leading to the decreased expression of MnSOD observed in many breast cancers.
Advances in Animal and Veterinary Sciences, 2016
C anine mammary cancer is an important neoplastic condition of female dogs (Davidson, 2003; Murphy, 2008; Salas et al., 2015) accounting for more than 40% of all tumours diagnosed (Sleeckx et al., 2011; Beck et al., 2013). The mortality rates in dogs suffering with canine mammary cancer are atleast three times higher than human breast cancer (Egenvall et al., 2005; Shafiee et al., 2013). In recent years there has been alarming increase in incidence of canine mammary tumor cases due to interaction between genetic and environmental factors (Pharoah et al., 2004; Wang et al., 2012). Cancer onset typically encompasses alterations in the cellular growth and proliferation, production of reactive oxygen species (ROS), and DNA damage. Reactive oxygen species (ROS) produced endogenously play important role in development of cancers by inducing DNA damage and stimulating cell proliferation which leads to tumour promotion (Clair et al., 1996). Higher levels of ROS contribute to genetic instability, which ultimately results in the stepwise process of carcinogenesis. Further ROS also activate various cancer signalling pathways and transcription factors in tumour cells regulating proliferation, me-Short Communication Abstract | Cancer onset typically encompasses alterations in cellular proliferation, production of reactive oxygen species (ROS), and DNA damage. Manganese superoxide dismutase (MnSOD) is one of the key enzymes for controlling oxidative stress. The role of MnSOD in cancer development is complex. Although initially considered as a tumour suppressor protein, recently it has been looked upon as a potential marker for cancer metastasis. Though MnSOD has been studied extensively in human cancers, not much work has been done for elucidating its role in dog cancers. Further dog MnSOD gene has not been sequenced so far, although dog MnSOD gene sequence predicted using computational biology approaches is present in the GenBank database. Therefore in this study, full-length ORF of sod2 gene, a gene encoding MnSOD enzyme, from a case of canine mixed mammary capillary cystic adenocarcinoma was cloned and sequenced. The sequence showed 100% similarity with the predicted dog MnSOD sequence present in GenBank database based on computational algorithms. Comparison of deduced amino acid sequence from Canis lupus familiaris and Homo sapiens revealed 92% similarity, confirming the conserved nature of the protein. Further the full-length MnSOD was expressed in E.coli and purified protein was isolated successfully. The recombinant MnSOD from dog offers a new tool for studying effect of the anti-oxidant enzyme on dog cancer cells, wound healing and other disorders.
Genetic polymorphism of manganese superoxide dismutase (MnSOD) and breast cancer susceptibility
Cell Biochemistry and Function, 2004
Within mitochondria, manganese superoxide dismutase (MnSOD) provides a major defence against oxidative damage by reactive oxygen species (ROS). An alanine-9valine (Ala-9Val) polymorphism in the mitochondrial targeting sequence of MnSOD has been described and has recently been associated with risk of human breast cancer. Our present case-control study was performed to explore the association between MnSOD genetic polymorphism and individual susceptibility to breast cancer. Ala-9Val polymorphism in the signal sequence of the protein for MnSOD was determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a study population. There was no significant difference in risk for breast cancer development between patients positive and negative for the MnSOD Ala allele with adjusted odds ratio (OR): 0.86 (95% confidence interval (CI) 0.43 to 1.72). When MnSOD Ala was combined with either cytochrome P450 1B1 CYP1B1*1 and catechol O-methyltransferase COMT-L (V158M) genotypes, the risk for developing breast cancer was significantly increased in patients with a body mass index (BMI) greater than 24 kg m À2 (OR: 1.42 (95%CI ¼ 1.04-1.93)).