Manganese superoxide dismutase in breast cancer: From molecular mechanisms of gene regulation to biological and clinical significance

doi:10.1016/j.freeradbiomed.2014.08.026

Free Radical Biology and Medicine

Volume 77, December 2014, Pages 139-151

https://doi.org/10.1016/j.freeradbiomed.2014.08.026 Get rights and content

Highlights

•
This is a comprehensive review of MnSOD in breast tumor growth and metastasis.
•
Mechanisms explaining altered MnSOD expression in breast tumor cells are described.
•
The role of MnSOD in breast tumor growth and metastasis is related to signaling pathways.
•
Clinical perspectives associating all findings reported in this review are proposed.

Abstract

Breast cancer is one of the most common malignancies of all cancers in women worldwide. Many difficulties reside in the prediction of tumor metastatic progression because of the lack of sufficiently reliable predictive biological markers, and this is a permanent preoccupation for clinicians. Manganese superoxide dismutase (MnSOD) may represent a rational candidate as a predictive biomarker of breast tumor metastatic progression, because its gene expression is profoundly altered between early and advanced breast cancer, in contrast to expression in the normal mammary gland. In this review, we report the characterization of some gene polymorphisms and molecular mechanisms of SOD2 gene regulation, which allows a better understanding of how MnSOD is decreased in early breast cancer and increased in advanced breast cancer. Several studies display the biological significance of MnSOD level in proliferation as well as in invasive and angiogenic abilities of breast tumor cells by controlling superoxide anion radical (O₂^•−) and hydrogen peroxide (H₂O₂). Particularly, they report how these reactive oxygen species may activate some signaling pathways involved in breast tumor growth. Emerging understanding of these findings provides an interesting framework for guiding translational research and suggests a way to define precisely the clinical interest of MnSOD as a prognostic and/or predicting marker in breast cancer, by associating with some regulators involved in SOD2 gene regulation and other well-known biomarkers, in addition to the typical clinical parameters.

Graphical abstract

Introduction

Today breast cancer represents the most frequent of all cancer pathologies in the world, with more than 1 million newly diagnosed cases and about 373,000 cancer-related deaths in women each year, despite all the significant progress in its diagnosis and treatment. Molecular mechanisms leading to growth and metastasis progression of breast tumors have not been clearly identified. In addition, a number of risk factors such as reproductive and hormonal factors, alcohol consumption, tobacco smoke, dietary factors, and chronic inflammation have been identified for breast cancer, but the mechanisms by which they increase the risk of the disease are not always clear [1]. It has been proposed that the production of reactive oxygen species (ROS) leading to oxidative stress is the linking factor between these carcinogens. Whereas high levels of ROS participate in the genetic instability leading to the multistep process of carcinogenesis, they also contribute to breast cancer progression, by activating various signaling pathways and redox-sensitive transcription factors in tumor cells, which regulate angiogenesis, proliferation, and metastasis [2].

ROS, such as superoxide anion radical (O₂^•−), hydrogen peroxide (H₂O₂), or hydroxyl radical (OH^•), are formed as a by-product of several cellular processes, particularly the electron transport chain in mitochondria, as well as environmental exposure [3]. The levels of O₂^•− and H₂O₂ are also determined by the balance between ROS-generating and antioxidant systems in cancer cells [4]. In this review, the origin and role of O₂^•− and H₂O₂ will be limited to the breast tumor growth and not to the early mutagenic events leading to cell transformation.

In the case of breast cancer, O₂^•− and H₂O₂ may be generated particularly from estrogen metabolism through catechol estrogen redox cycling [5]. In addition, changes in the expression of antioxidant enzymes, leading to an imbalance between them, have often been observed in breast cancer cells, compared to noncancerous cells [6]. Among them, the manganese-dependent superoxide dismutase (MnSOD) is well known to have an altered expression in breast cancer, as in many other cancers [7], [8], [9], [10], [11], [12], [13]. This mitochondrial enzyme possesses a typical mitochondrial leader sequence in the N-terminal region allowing the apoprotein to be translocated rapidly into the matrix of the organelle and to convert mitochondrial-generated O₂^•− from the respiratory chain to H₂O₂ [14], [15]. In contrast to cytosolic and extracellular Cu/ZnSOD expressed also in human cells, MnSOD is considered one of the most important antioxidant enzymes, because MnSOD-knockout mice have severe metabolic acidosis and degeneration of neurons and cardiac myocytes and die prenatally from dilated cardiomyopathy [16]. This antioxidant enzyme is cytoprotective and plays an antiapoptotic role against oxidative stress, ionizing radiation, and inflammatory cytokines [17], [18].

Transformation of breast epithelial cells is a multistep process in which ROS are involved and may be exacerbated by a low intracellular MnSOD activity, which depends on SOD2 genetic polymorphisms. Among other SOD isoforms, these identified genetic polymorphisms may be associated with a predisposition to a greater risk of breast cancer [19].

In contrast to normal cells, MnSOD expression is often altered at the transcriptional level in breast tumors and cancer cell lines. This alteration in MnSOD expression is often associated with that of H₂O₂-detoxifying enzymes in breast tumor cells, leading to an imbalance in the redox state by an increase in the level of O₂^•− or H₂O₂ and its consequences on tumor growth [6]. Also, this review intends to provide a comprehensive picture of MnSOD and the regulation of its gene for a better understanding of how this antioxidant enzyme plays a role in breast tumor growth and may have a clinical interest.

Section snippets

Structure and transcriptional regulation of the SOD2 gene

MnSOD expression, which is encoded by the nuclear SOD2 gene located on chromosome 6q25, is inducible by many transcription factors able to bind the proximal promoter and highly regulated in normal cells [20], [21]. The SOD2 gene consists of five exons interrupted by four introns and characterized by a 5′-proximal promoter lacking a TATA or CAAT box but containing a GC-rich region [22]. Regulatory regions of the SOD2 gene are divided into numerous upstream regulatory elements, the GC-rich region

Relation between SOD2 genetic polymorphism and breast cancer risk

Even if O₂^•− is not an especially reactive agent itself, it serves for the generation of other ROS such as H₂O₂ and peroxynitrite. Cells need antioxidant enzymes to remove O₂^•− and H₂O₂ to avoid deleterious effects that can promote cell transformation. Also, low MnSOD activity, depending on SOD2 genetic polymorphisms, may contribute to the breast carcinogenesis process. From a large number of studies in diverse populations, a relation between low MnSOD activity and risk of breast cancer

Relation between MnSOD expression and breast tumor growth

Altered MnSOD levels have been found in many cancer cells from the early stage of carcinogenesis. Increased or decreased levels of MnSOD have been reported in tumor cells, compared to their normal counterparts, which depends on cancer type and tumor grade [7], [8], [9], [10], [11], [12], [13]. Concerning breast cancer, MnSOD is differentially expressed in tumor cell lines as well as in tumor samples from patients. We observed that this distinct MnSOD expression is dependent on estrogen receptor

Transcriptional downregulation of the SOD2 gene

Breast cancer cells display altered basal transcription of the SOD2 gene, which may be either upregulated or repressed in tumor cells, depending on the malignant phenotype. It has been described that the downregulated expression of the SOD2 gene in cancer cells may be due, in part, to defects in transcriptional regulation of the gene, because of mutations in the proximal promoter [41], epigenetic processes [26], or high expression of repressive transcription factors [33]. Some molecular

Effect of MnSOD on the cell cycle

In addition to the fact that cell cycle progression of proliferative normal cells is strictly regulated by a sequential activation of cyclin-dependent kinases (CDKs), regulated by CDK inhibitors, MnSOD may be considered a novel regulator of the cell cycle. Its expression changes during cell cycle progression. In addition, MnSOD expression is lower in highly proliferative normal cells than in quiescent or differentiated cells. It has been observed recently in mouse embryonic fibroblasts that

Role of MnSOD in angiogenic activity of breast tumor cells

Tumoral angiogenesis is essential for the growth and spread of breast tumor cells. There are several different angiogenic growth factors associated with tumoral angiogenesis in breast cancer, but the major mediator is vascular endothelial growth factor (VEGF), a homodimeric heparin-binding glycoprotein whose gene is mainly targeted by HIF transcription factor [101], [102]. This factor is activated by a reduced oxygen availability, which may be caused by a high rate of cell proliferation

The link between MnSOD and invasive abilities of breast cancer cells

High MnSOD expression, dependent on constitutive NF-κB activity and the lack of DDB2 and AP-2α expression (Fig. 2B), is correlated with the invasive and the metastatic properties of breast cancer cells and is coupled to an imbalance in H₂O₂-detoxifying antioxidant enzyme expression (Fig. 4), thus promoting an accumulation of H₂O₂ in these aggressive cells [4], [6]. Several studies report that the role of MnSOD in invasive properties of aggressive breast cancer cells is mediated by H₂O₂, because

Conclusions and clinical perspectives

The role of MnSOD in cancer, including breast cancer, has been greatly studied and is associated with profound alterations in SOD2 gene expression by various molecular mechanisms. This review summarized main findings that bring a new understanding of breast tumor growth and how breast cancer cells progress toward an invasive phenotype according to MnSOD levels. Distinct SOD2 gene expression between normal mammary epithelium and early stages of breast tumors leads us to postulate that MnSOD

Acknowledgments

The authors are grateful to the following financial supporters: the Ligue contre le Cancer (Comités Meuse and Vosges), the University of Lorraine, and Région Lorraine. C. Barbieux and R. Klotz have a fellowship from the French Research Ministry. The authors are also grateful to Professor S.N. Thornton for critical reading of the manuscript.

References (140)

K. Mitrunen et al.
Molecular epidemiology of sporadic breast cancer: the role of polymorphic genes involved in oestrogen biosynthesis and metabolism
Mutat. Res.
(2003)
L. Vera-Ramirez et al.
Free radicals in breast carcinogenesis, breast cancer progression and cancer stem cells: biological bases to develop oxidative-based therapies
Crit. Rev. Oncol. Hematol.
(2011)
V. Sosa et al.
Oxidative stress and cancer: an overview
Ageing Res. Rev.
(2013)
L.A. Ridnour et al.
Tumor suppressive effects of MnSOD overexpression may involve imbalance in peroxide generation versus peroxide removal
Antioxid. Redox Signaling
(2004)
V. Okoh et al.
Estrogen-induced reactive oxygen species-mediated signalings contribute to breast cancer
Biochim. Biophys. Acta
(2011)
Z. Kattan et al.
Role of manganese superoxide dismutase on growth and invasive properties of human estrogen-independent breast cancer cells
Breast Cancer Res. Treat.
(2008)
S. Nishida et al.
Manganese superoxide dismutase content and localization in human thyroid tumours
J. Pathol.
(1993)
C.S. Cobbs et al.
Manganese superoxide dismutase expression in human central nervous system tumors
Cancer Res.
(1996)
M. Landriscina et al.
The level of MnSOD is directly correlated with grade of brain tumours of neuroepithelial origin
Br. J. Cancer
(1996)
K. Kahlos et al.
Manganese superoxide dismutase in healthy human pleural mesothelium and in malignant pleural mesothelioma
Am. J. Respir. Cell Mol. Biol.
(1998)

A.M. Janssen et al.

Superoxide dismutases in gastric and esophageal cancer and the prognostic impact in gastric cancer

Clin. Cancer Res.

(2000)

M. Malafa et al.

MnSOD expression is increased in metastatic gastric cancer

J. Surg. Res.

(2000)

Y. Hu et al.

Mitochondrial manganese-superoxide dismutase expression in ovarian cancer: role in cell proliferation and response to oxidative stress

J. Biol. Chem.

(2005)

R.A. Weisiger et al.

Mitochondrial superoxide dismutase: site of synthesis and intramitochondrial localization

J. Biol. Chem.

(1973)

A. Okado-Matsumoto et al.

Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria

J. Biol. Chem.

(2001)

R.M. Lebovitz et al.

Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice

Proc. Natl. Acad. Sci. USA

(1996)

D.K. Clair et al.

Suppression of radiation-induced neoplastic transformation by overexpression of mitochondrial superoxide dismutase

Mol. Carcinog.

(1992)

K.K. Kiningham et al.

Overexpression of manganese superoxide dismutase protects against mitochondrial-initiated poly(ADP-ribose) polymerase-mediated cell death

FASEB J.

(1999)

C.G. Bica et al.

MnSOD gene polymorphism association with steroid-dependent cancer

Pathol. Oncol. Res.

(2009)

S.L. Church et al.

Sublocalization of the gene encoding manganese superoxide dismutase (MnSOD/SOD2) to 6q25 by fluorescence in situ hybridization and somatic cell hybrid mapping

Genomics

(1992)

S.K. Dhar et al.

Manganese superoxide dismutase regulation and cancer

Free Radic. Biol. Med.

(2012)

X.S. Wan et al.

Molecular structure and organization of the human manganese superoxide dismutase gene

DNA Cell Biol

(1994)

K. Maehara et al.

Cooperative interaction of NF-kappaB and C/EBP binding sites is necessary for manganese superoxide dismutase gene transcription mediated by lipopolysaccharide and interferon-gamma

FEBS Lett.

(1999)

Y. Xu et al.

An intronic NF-kappaB element is essential for induction of the human manganese superoxide dismutase gene by tumor necrosis factor-alpha and interleukin-1beta

DNA Cell Biol

(1999)

X. Qiu et al.

Distinct functions of CCAAT enhancer-binding protein isoforms in the regulation of manganese superoxide dismutase during interleukin-1beta stimulation

J. Biol. Chem.

(2008)

A.R. Cyr et al.

Regulation of SOD2 in cancer by histone modifications and CpG methylation: closing the loop between redox biology and epigenetics

Antioxid. Redox Signaling

(2013)

H.P. Kim et al.

Transcriptional activation of the human manganese superoxide dismutase gene mediated by tetradecanoylphorbol acetate

J. Biol. Chem.

(1999)

A. Bianchi et al.

Induction of MnSOD gene by arachidonic acid is mediated by reactive oxygen species and p38 MAPK signaling pathway in human HepG2 hepatoma cells

Free Radic. Biol. Med.

(2002)

Y. Zhao et al.

Detection of the content and activity of the transcription factor AP-1 in a multistage skin carcinogenesis model

Methods Mol. Biol.

(2003)

G.J. Kops et al.

Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress

Nature

(2002)

S. Porntadavity et al.

TPA-activated transcription of the human MnSOD gene: role of transcription factors Sp-1 and Egr-1

DNA Cell Biol

(2001)

Y. Xu et al.

Transcriptional regulation of the human manganese superoxide dismutase gene: the role of specificity protein 1 (Sp1) and activating protein-2 (AP-2)

Biochem. J.

(2002)

C.H. Zhu et al.

A family of AP-2 proteins down-regulate manganese superoxide dismutase expression

J. Biol. Chem.

(2001)

K. Maehara et al.

Early growth-responsive-1-dependent manganese superoxide dismutase gene transcription mediated by platelet-derived growth factor

FASEB J.

(2001)

S.K. Dhar et al.

Identification of nucleophosmin as an NF-kappaB co-activator for the induction of the human SOD2 gene

J. Biol. Chem.

(2004)

Y. Xu et al.

The role of a single-stranded nucleotide loop in transcriptional regulation of the human sod2 gene

J. Biol. Chem.

(2007)

M.K. Kwak et al.

Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione

Mol. Med.

(2001)

S.P. Hussain et al.

p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis

Cancer Res.

(2004)

Y. Huang et al.

Decreased expression of manganese superoxide dismutase in transformed cells is associated with increased cytosine methylation of the SOD2 gene

DNA Cell Biol

(1999)

K. Maehara et al.

Effects of histone acetylation on transcriptional regulation of manganese superoxide dismutase gene

Biochem. Biophys. Res. Commun.

(2002)

Y. Xu et al.

Mutations in the promoter reveal a cause for the reduced expression of the human manganese superoxide dismutase gene in cancer cells

Oncogene

(1999)

A. Sutton et al.

The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria

Pharmacogenetics

(2003)

B.L. McAtee et al.

Manganese superoxide dismutase: effect of the ala16val polymorphism on protein, activity, and mRNA levels in human breast cancer cell lines and stably transfected mouse embryonic fibroblasts

Mol. Cell. Biochem.

(2010)

M. Bergman et al.

Polymorphism in the manganese superoxide dismutase (MnSOD) gene and risk of breast cancer in young women

J. Cancer Res. Clin. Oncol.

(2005)

R.C. Millikan et al.

Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case–control study of African Americans and whites

Breast Cancer Res.

(2004)

S. Wang et al.

Association between manganese superoxide dismutase (MnSOD) Val-9Ala polymorphism and cancer risk—a meta-analysis

Eur. J Cancer

(2009)

D.G. Cox et al.

Gene × gene interaction between MnSOD and GPX-1 and breast cancer risk: a nested case–control study

BMC Cancer

(2006)

R. Brigelius-Flohé et al.

Glutathione peroxidases

Biochim. Biophys. Acta

(2013)

D.G. Cox et al.

No association between GPX1 Pro198Leu and breast cancer risk

Cancer Epidemiol. Biomarkers Prev

(2004)

J. Hu et al.

GPX1 Pro198Leu polymorphism and breast cancer risk: a meta-analysis

Breast Cancer Res. Treat.

(2010)

Cited by (83)

The impact of physical activity on promoter-specific methylation of genes involved in the redox-status and disease progression: A longitudinal study on post-surgery female breast cancer patients undergoing medical treatment
2024, Redox Biology
Most anticancer treatments act on oxidative-stress pathways by producing reactive oxygen species (ROS) to kill cancer cells, commonly resulting in consequential drug-induced systemic cytotoxicity. Physical activity (PA) has arisen as an integrative cancer therapy, having positive health effects, including in redox-homeostasis. Here, we investigated the impact of an online supervised PA program on promoter-specific DNA methylation, and corresponding gene expression/activity, in 3 antioxidants- (SOD1, SOD2, and CAT) and 3 breast cancer (BC)-related genes (BRCA1, L3MBTL1 and RASSF1A) in a population-based sample of women diagnosed with primary BC, undergoing medical treatment. We further examined mechanisms involved in methylating and demethylating pathways, predicted biological pathways and interactions of exercise-modulated molecules, and the functional relevance of modulated antioxidant markers on parameters related to aerobic capacity/endurance, physical fatigue and quality of life (QoL).
PA maintained levels of SOD activity in blood plasma, and at the cellular level significantly increased SOD2 mRNA (≈+77 %), contrary to their depletion due to medical treatment. This change was inversely correlated with DNA methylation in SOD2 promoter (≈−20 %). Similarly, we found a significant effect of PA only on L3MBTL1 promoter methylation (≈−25 %), which was inversely correlated with its mRNA (≈+43 %). Finally, PA increased TET1 mRNA levels (≈+15 %) and decreased expression of DNMT3B mRNA (≈−28 %).
Our results suggest that PA-modulated DNA methylation affects several signalling pathways/biological activities involved in the cellular oxidative stress response, chromatin organization/regulation, antioxidant activity and DNA/protein binding. These changes may positively impact clinical outcomes and improve the response to cancer treatment in post-surgery BC patients.
Therapeutic effect of trace elements on multiple myeloma and mechanisms of cancer process
2023, Food and Chemical Toxicology
In the human body, trace elements and other micronutrients play a vital role in growth, health and immune system function. The trace elements are Iron, Manganese, Copper, Iodine, Zinc, Cobalt, Fluoride, and Selenium. Estimating the serum levels of trace elements in hematologic malignancy patients can determine the severity of the tumor. Multiple myeloma (MM) is a hematopoietic malignancy and is characterized by plasma cell clonal expansion in bone marrow. Despite the advances in treatment methods, myeloma remains largely incurable. In addition to conventional medicine, treatment is moving toward less expensive noninvasive alternatives. One of the alternative treatments is the use of dietary supplements. In this review, we focused on the effect of three trace elements including iron, zinc and selenium on important mechanisms such as the immune system, oxidative and antioxidant factors and cell cycle. Using some trace minerals in combination with approved drugs can increase patients' recovery speed. Trace elements can be used as not only a preventive but also a therapeutic tool, especially in reducing inflammation in hematological cancers such as multiple myeloma. We hope that the prospect of the correct use of trace element supplements in the future could be promising for the treatment of diseases.
Comparison of tear proteomic and neuromediator profiles changes between small incision lenticule extraction (SMILE) and femtosecond laser-assisted in-situ keratomileusis (LASIK)
2021, Journal of Advanced Research
The tear proteomics and neuromediators are associated with clinical dry eye parameters following refractive surgery.
To investigate and compare the tear proteomic and neuromediator profiles following small incision lenticule extraction (SMILE) versus laser-assisted in-situ keratomileusis (LASIK).
In this randomized controlled trial with paired-eye design, 70 patients were randomized to receive SMILE in one eye and LASIK in the other eye. Tear samples were collected preoperatively, and 1 week, 1, 3, 6 and 12 months postoperatively, and were examined for protein concentration changes using sequential window acquisition of all theoretical fragment ion mass spectrometry (SWATH-MS). The data were analyzed with DAVID Bioinformatics Resources for enriched gene ontology terms and over-represented pathways. Tear neuromediators levels were correlated with clinical parameters.
Post-SMILE eyes had significantly better Oxford staining scores and tear break-up time (TBUT) than post-LASIK eyes at 1 and 3 months, respectively. Tear substance P and nerve growth factor levels were significantly higher in the LASIK group for 3 months and 1 year, respectively. SMILE and LASIK shared some similar biological responses postoperatively, but there was significant up-regulation in leukocyte migration and wound healing at 1 week, humoral immune response and apoptosis at 1 month, negative regulation of endopeptidase activity at 3 to 6 months, and extracellular structure organization at 1 year in the post-LASIK eyes. Tear mucin-like protein 1 and substance P levels were significantly correlated with TBUT (r = -0.47, r = -0.49, respectively).
Significant differences in the tear neuromediators and proteomics were observed between SMILE and LASIK, even though clinical dry eye signs have subsided and became comparable between 2 procedures.
Proapoptotic activity induced by photodynamic reaction with novel cyanine dyes in caspase-3-deficient human breast adenocarcinoma cell lines (MCF/WT and MCF/DX)
2020, Photodiagnosis and Photodynamic Therapy
Photodynamic therapy (PDT) is currently one of the cancer treatment options. PDT requires the application of a photosensitizer (such as: porphyrins, chlorines, and phthalocyanines) that selectively targets malignant cells. It is a dilemma to find a proper photosensitizer. In our study, we have tested a new in-vitro group of cyanine dyes. These dyes are widely applied in biotechnology as fluorescent markers.
Two malignant adenocarcinoma cell lines (MCF-7/WT and MCF-7/DOX) were investigated using photodynamic reaction (PDR) with four cyanine dyes (KF-570, HM-118, FBF-749, and ER-139). KF-570 and HM-118 were irradiated with red light (630 nm), whereas FBF-749 and ER-139 with green light (435 nm). To evaluate PDR efficiency, a clonogenic test was conducted. Apoptosis was investigated by TUNEL and NCA (neutral comet) assays. Proteins selected as indicators of the apoptotic pathway (AIF, sPLA2, Smac/Diablo) and intracellular response markers (SOD-1 and GST-pi) were detected using western blot. The highest number of apoptotic cells (ca. 100%) was observed after PDR with HM-118 and KF-570 in both conducted tests, in both cell lines. The results showed that HM-118 and KF-570 cyanine dyes demonstrated a major phototoxic effect causing apoptosis in doxorubicin-resistant and sensitive cell lines.
Antioxidant Enzymes in Cancer Cells: Their Role in Photodynamic Therapy Resistance and Potential as Targets for Improved Treatment Outcomes
2024, International Journal of Molecular Sciences
Methyltransferase METTL3-mediated maturation of miR-4654 facilitates high glucose-induced apoptosis and oxidative stress in lens epithelial cells via decreasing SOD2
2024, Chemical Biology and Drug Design

View all citing articles on Scopus

View full text

Review ArticleManganese superoxide dismutase in breast cancer: From molecular mechanisms of gene regulation to biological and clinical significance

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Structure and transcriptional regulation of the SOD2 gene

Relation between SOD2 genetic polymorphism and breast cancer risk

Relation between MnSOD expression and breast tumor growth

Transcriptional downregulation of the SOD2 gene

Effect of MnSOD on the cell cycle

Role of MnSOD in angiogenic activity of breast tumor cells

The link between MnSOD and invasive abilities of breast cancer cells

Conclusions and clinical perspectives

Acknowledgments

Molecular epidemiology of sporadic breast cancer: the role of polymorphic genes involved in oestrogen biosynthesis and metabolism

Mutat. Res.

Free radicals in breast carcinogenesis, breast cancer progression and cancer stem cells: biological bases to develop oxidative-based therapies

Crit. Rev. Oncol. Hematol.

Oxidative stress and cancer: an overview

Ageing Res. Rev.

Tumor suppressive effects of MnSOD overexpression may involve imbalance in peroxide generation versus peroxide removal

Antioxid. Redox Signaling

Estrogen-induced reactive oxygen species-mediated signalings contribute to breast cancer

Biochim. Biophys. Acta

Role of manganese superoxide dismutase on growth and invasive properties of human estrogen-independent breast cancer cells

Breast Cancer Res. Treat.

Manganese superoxide dismutase content and localization in human thyroid tumours

J. Pathol.

Manganese superoxide dismutase expression in human central nervous system tumors

Cancer Res.

The level of MnSOD is directly correlated with grade of brain tumours of neuroepithelial origin

Br. J. Cancer

Manganese superoxide dismutase in healthy human pleural mesothelium and in malignant pleural mesothelioma

Am. J. Respir. Cell Mol. Biol.

Superoxide dismutases in gastric and esophageal cancer and the prognostic impact in gastric cancer

Clin. Cancer Res.

MnSOD expression is increased in metastatic gastric cancer

J. Surg. Res.

Mitochondrial manganese-superoxide dismutase expression in ovarian cancer: role in cell proliferation and response to oxidative stress

J. Biol. Chem.

Mitochondrial superoxide dismutase: site of synthesis and intramitochondrial localization

J. Biol. Chem.

Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria

J. Biol. Chem.

Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice

Proc. Natl. Acad. Sci. USA

Suppression of radiation-induced neoplastic transformation by overexpression of mitochondrial superoxide dismutase

Mol. Carcinog.

Overexpression of manganese superoxide dismutase protects against mitochondrial-initiated poly(ADP-ribose) polymerase-mediated cell death

FASEB J.

MnSOD gene polymorphism association with steroid-dependent cancer

Pathol. Oncol. Res.

Sublocalization of the gene encoding manganese superoxide dismutase (MnSOD/SOD2) to 6q25 by fluorescence in situ hybridization and somatic cell hybrid mapping

Genomics

Manganese superoxide dismutase regulation and cancer

Free Radic. Biol. Med.

Molecular structure and organization of the human manganese superoxide dismutase gene

DNA Cell Biol

Cooperative interaction of NF-kappaB and C/EBP binding sites is necessary for manganese superoxide dismutase gene transcription mediated by lipopolysaccharide and interferon-gamma

FEBS Lett.

An intronic NF-kappaB element is essential for induction of the human manganese superoxide dismutase gene by tumor necrosis factor-alpha and interleukin-1beta

DNA Cell Biol

Distinct functions of CCAAT enhancer-binding protein isoforms in the regulation of manganese superoxide dismutase during interleukin-1beta stimulation

J. Biol. Chem.

Regulation of SOD2 in cancer by histone modifications and CpG methylation: closing the loop between redox biology and epigenetics

Antioxid. Redox Signaling

Transcriptional activation of the human manganese superoxide dismutase gene mediated by tetradecanoylphorbol acetate

J. Biol. Chem.

Induction of MnSOD gene by arachidonic acid is mediated by reactive oxygen species and p38 MAPK signaling pathway in human HepG2 hepatoma cells

Free Radic. Biol. Med.

Detection of the content and activity of the transcription factor AP-1 in a multistage skin carcinogenesis model

Methods Mol. Biol.

Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress

Nature

TPA-activated transcription of the human MnSOD gene: role of transcription factors Sp-1 and Egr-1

DNA Cell Biol

Transcriptional regulation of the human manganese superoxide dismutase gene: the role of specificity protein 1 (Sp1) and activating protein-2 (AP-2)

Biochem. J.

A family of AP-2 proteins down-regulate manganese superoxide dismutase expression

Review Article
Manganese superoxide dismutase in breast cancer: From molecular mechanisms of gene regulation to biological and clinical significance