Document Detail


Epigenetic reprogramming governs EcSOD expression during human mammary epithelial cell differentiation, tumorigenesis and metastasis.
MedLine Citation:
PMID:  23318435     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Expression of the antioxidant enzyme EcSOD in normal human mammary epithelial cells was not recognized until recently. Although expression of EcSOD was not detectable in non-malignant human mammary epithelial cells (HMEC) cultured in conventional two-dimensional (2D) culture conditions, EcSOD protein expression was observed in normal human breast tissues, suggesting that the 2D-cultured condition induces a repressive status of EcSOD gene expression in HMEC. With the use of laminin-enriched extracellular matrix (lrECM), we were able to detect expression of EcSOD when HMEC formed polarized acinar structures in a 3D-culture condition. Repression of the EcSOD-gene expression was again seen when the HMEC acini were sub-cultured as a monolayer, implying that lrECM-induced acinar morphogenesis is essential in EcSOD-gene activation. We have further shown the involvement of DNA methylation in regulating EcSOD expression in HMEC under these cell culture conditions. EcSOD mRNA expression was strongly induced in the 2D-cultured HMEC after treatment with a DNA methyltransferase inhibitor. In addition, epigenetic analyses showed a decrease in the degree of CpG methylation in the EcSOD promoter in the 3D versus 2D-cultured HMEC. More importantly, >80% of clinical mammary adenocarcinoma samples showed significantly decreased EcSOD mRNA and protein expression levels compared with normal mammary tissues and there is an inverse correlation between the expression levels of EcSOD and the clinical stages of breast cancer. Combined bisulfite restriction analysis analysis of some of the tumors also revealed an association of DNA methylation with the loss of EcSOD expression in vivo. Furthermore, overexpression of EcSOD inhibited breast cancer metastasis in both the experimental lung metastasis model and the syngeneic mouse model. This study suggests that epigenetic silencing of EcSOD may contribute to mammary tumorigenesis and that restoring the extracellular superoxide scavenging activity could be an effective strategy for breast cancer treatment.
Authors:
M L Teoh-Fitzgerald; M P Fitzgerald; W Zhong; R W Askeland; F E Domann
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-14
Journal Detail:
Title:  Oncogene     Volume:  33     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2014 Jan 
Date Detail:
Created Date:  2014-01-16     Completed Date:  2014-03-14     Revised Date:  2014-08-05    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  358-68     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Breast Neoplasms / genetics,  metabolism,  pathology
Cell Culture Techniques
Cell Differentiation / genetics*
Cell Line
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics*,  metabolism
Cells, Cultured
DNA Methylation*
Epigenesis, Genetic
Epithelial Cells / cytology,  metabolism*
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Lung Neoplasms / genetics,  metabolism,  secondary
Mammary Glands, Human / cytology,  metabolism
Mammary Neoplasms, Experimental / genetics,  metabolism,  pathology
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Staging
Reverse Transcriptase Polymerase Chain Reaction
Superoxide Dismutase / genetics*,  metabolism
Transplantation, Heterologous
Grant Support
ID/Acronym/Agency:
P30 ES005605/ES/NIEHS NIH HHS; R01 CA073612/CA/NCI NIH HHS; R01 CA073612/CA/NCI NIH HHS; R01 CA115438/CA/NCI NIH HHS; R01 CA115438/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
EC 1.15.1.1/SOD3 protein, human; EC 1.15.1.1/Sod3 protein, mouse; EC 1.15.1.1/Superoxide Dismutase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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