Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors.
Only about 5% of human breast cancers can be attributed to inheritance of breast cancer susceptibility genes, while the balance are considered to be sporadic in origin. Breast cancer incidence varies with diet and other environmental influences, including carcinogen exposure. However, the effects of environmental carcinogens on cell growth control pathways are poorly understood. Here we have examined oncogenic signaling pathways that are activated in mammary tumors in mice treated with the prototypical polycyclic aromatic hydrocarbon (PAH) 7,12-dimethylbenz[a]anthracene (DMBA). In female FVB mice given 6 doses of 1 mg of DMBA by weekly gavage beginning at 5 weeks of age, all of the mice developed tumors by 34 weeks of age (median 20 weeks after beginning DMBA); 75% of the mice had mammary tumors. DMBA-induced mammary tumors exhibited elevated expression of the aryl hydrocarbon receptor (AhR), c-myc, cyclin D1, and hyperphosphorylated retinoblastoma (Rb) protein. Because of this, the activation of upstream regulatory pathways was assessed, and elements of the Wnt signaling pathway, the NF-kappa B pathway, and the prolyl isomerase Pin-1 were found to be frequently up-regulated in the tumors when compared to normal mammary gland controls. These data suggest that environmental carcinogens can produce long-lasting alterations in growth and anti-apoptotic pathways, leading to mammary tumorigenesis.
Currier
Nicolas
N
Boston University School of Medicine, Department of Medicine, Boston, MA, USA.
Solomon
Sandra E
SE
Demicco
Elizabeth G
EG
Chang
Donny L F
DL
Farago
Marganit
M
Ying
Haoqiang
H
Dominguez
Isabel
I
Sonenshein
Gail E
GE
Cardiff
Robert D
RD
Xiao
Zhi-Xiong Jim
ZX
Sherr
David H
DH
Seldin
David C
DC
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens; D047390:Casein Kinase II / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019940:Genes, bcl-1 / Q000187:drug effects / Q000502:physiology; D016259:Genes, myc / Q000187:drug effects / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009857:Oncogenes / Q000187:drug effects / Q000502:physiology*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D002273:Carcinogens; D016328:NF-kappa B; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D016160:Retinoblastoma Protein; D051153:Wnt Proteins; D051176:beta Catenin; D015127:9,10-Dimethyl-1,2-benzanthracene; D004247:DNA; D047390:Casein Kinase II; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse