Molecular mechanisms of the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced inverted U-shaped dose responsiveness in anchorage independent growth and cell proliferation of human breast epithelial cells with stem cell characteristics.
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.
Ahn
Nam-Shik
NS
Laboratory of Stem Cell and Tumor Biology, Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, San 56-1 Sillim-Dong, Kwanak-Gu, Seoul 151-742, Republic of Korea.
Hu
Hongbo
H
Park
Jin-Sung
JS
Park
Joon-Suk
JS
Kim
Jong-Sik
JS
An
Sungwhan
S
Kong
Gu
G
Aruoma
Okezie I
OI
Lee
Yong-Soon
YS
Kang
Kyung-Sun
KS
D001940:Breast / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology*; D014410:Tumor Stem Cell Assay; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
D002273:Carcinogens; D007375:Interleukin-1; D017396:Plasminogen Activator Inhibitor 2; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D019363:Cytochrome P-450 CYP1A1; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases