Abstract
Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has a variety of carcinogenic and noncarcinogenic effects in experimental animals, its role in human carcinogenicity remain controversial. A simian virus 40-immortalized cell line from normal human breast epithelial cells with stem cells and luminal characteristics (M13SV1) was used to study whether TCDD can induce AIG positive colony formation and cause increased cell numbers in a inverted U-shaped dose-response manner. TCDD activated Akt, ERK2, and increased the expression of CYP1A1, PAI-2, IL-lb mRNA, and ERK2 protein levels. TCDD was able to increased phosphorylation and expression of ERK2 in same dose-response manner as AIG positive colony formation. Thus, TCDD induced tumorigenicity in M13SV1, possibly through the phosphorylation of ERK2 and/or Akt. Further, cDNA microarray with 7448 sequence-verified clones was used to profile various gene expression patterns after treatment of TCDD. Three clear patterns could be delineated: genes that were dose-dependently up-regulated, genes expressed in either U-shape and/or inverted U-shape. The fact that these genes are intrinsically related to breast epithelial cell proliferation and survival clearly suggests that they may be involved in the TCDD-induced breast tumorigenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Breast / cytology*
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Breast / drug effects
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Breast / metabolism
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Carcinogens / toxicity
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Cell Line, Transformed
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Cell Proliferation / drug effects
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Cytochrome P-450 CYP1A1 / drug effects
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Cytochrome P-450 CYP1A1 / genetics
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / pathology
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Gene Expression Regulation / drug effects
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Humans
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Interleukin-1 / genetics
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Mitogen-Activated Protein Kinase 1 / drug effects
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / drug effects
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mitogen-Activated Protein Kinase 8 / drug effects
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Mitogen-Activated Protein Kinase 8 / metabolism
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Oligonucleotide Array Sequence Analysis
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Phosphorylation
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Plasminogen Activator Inhibitor 2 / genetics
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Polychlorinated Dibenzodioxins / toxicity*
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Proto-Oncogene Proteins c-akt / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / drug effects
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Stem Cells / cytology*
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Tumor Stem Cell Assay
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p38 Mitogen-Activated Protein Kinases / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Carcinogens
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Interleukin-1
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Plasminogen Activator Inhibitor 2
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Polychlorinated Dibenzodioxins
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RNA, Messenger
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Cytochrome P-450 CYP1A1
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase 8
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p38 Mitogen-Activated Protein Kinases