Document Detail


Induction by 7,12-dimethylbenz(a)anthracene of molecular and biochemical alterations in transformed human mammary epithelial stem cells, and protection by N-acetylcysteine.
MedLine Citation:
PMID:  16865267     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Several lines of evidence suggest that stem cells are major targets for carcinogens. A normal human breast epithelial cell type was previously shown to possess stem cell characteristics. Further cell lines were derived following sequential transfection with SV40 large T-antigen (immortal, non-tumorigenic M13SV1 cells), exposure to X-rays (weakly tumorigenic M13SV1R2 cells), and ectopic expression of c-erbB2/neu (highly tumorigenic M13SV1R2N1 cells). We evaluated some characteristics of these cells and their susceptibility to the breast carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Compared to M13SV1 cells, the two untreated tumorigenic cell lines displayed higher levels of connexin 43 expression and NF-kappaB nuclear translocation, and a higher frequency of fhit loss. The baseline nuclear translocation of AP-1 and pCREB was particularly evident in M13SV1R2N1 cells and was further enhanced by DMBA treatment, indicating an interaction between c-erbB2/neu and DMBA-induced signalling. Treatment with DMBA did neither affect the baseline fhit loss nor p53 mutation, whereas it increased NF-kappaB nuclear translocation, the proportion of apoptotic cells, and the levels of connexin 43, common 4977-bp mitochondrial DNA deletion, and bulky adducts to nuclear DNA. DMBA-treated M13SV1 cells underwent significant oxidative DNA damage and exhibited the highest DNA adduct levels, while they had the lowest apoptotic rate. Co-treatment of cells with N-acetylcysteine (NAC) attenuated DMBA-induced toxicity and DNA alterations, particularly in M13SV1 cells. Thus, the immortal cell line derived from the normal human adult breast stem cell without further tumorigenic progression is the most susceptible both to DMBA-related alterations and to the protective effects of NAC.
Authors:
Silvio De Flora; Sonia Scarfì; Alberto Izzotti; Francesco D'Agostini; Chia-Cheng Chang; Maria Bagnasco; Antonio De Flora; James E Trosko
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of oncology     Volume:  29     ISSN:  1019-6439     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2006 Sep 
Date Detail:
Created Date:  2006-07-25     Completed Date:  2006-10-05     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  521-9     Citation Subset:  IM    
Affiliation:
Department of Health Sciences, Section of Hygiene and Preventive Medicine, University of Genoa, I-16132 Genoa, Italy. sdf@unige.it
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MeSH Terms
Descriptor/Qualifier:
9,10-Dimethyl-1,2-benzanthracene / toxicity*
Acetylcysteine / pharmacology*
Acid Anhydride Hydrolases / metabolism
Apoptosis / drug effects
Carcinogens / toxicity*
Cell Line, Transformed
Cell Nucleus
Cells, Cultured
Connexin 43 / metabolism
Epithelial Cells / drug effects*,  metabolism
Free Radical Scavengers / pharmacology*
Humans
Mammary Glands, Human / drug effects*,  metabolism
NF-kappa B / genetics,  metabolism
Neoplasm Proteins / metabolism
Protein Transport
Receptor, erbB-2 / metabolism
Stem Cells / drug effects*,  metabolism
Tumor Suppressor Protein p53 / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
PA42 ES049111/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Carcinogens; 0/Connexin 43; 0/Free Radical Scavengers; 0/NF-kappa B; 0/Neoplasm Proteins; 0/Tumor Suppressor Protein p53; 0/fragile histidine triad protein; 57-97-6/9,10-Dimethyl-1,2-benzanthracene; 616-91-1/Acetylcysteine; EC 2.7.10.1/Receptor, erbB-2; EC 3.6.-/Acid Anhydride Hydrolases

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