Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesis.
Mouse mammary tumorigenesis is greatly influenced by a variety of exogenous agents, such as MMTV, chemical carcinogens (i.e., polycyclic aromatic hydrocarbons), and radiation, as well as by endogenous/physiological factors, such as steroid hormones, tumor-suppressor genes (i.e., Brca1/2, p53), and gene products of modifier genes. In the mouse model, the most frequently used chemical carcinogen has been 7,12-dimethylbenz[a]anthracene (DMBA), which activates the Ha-ras gene but does not alter the p53 tumor-suppressor gene. However, on an existing background of p53 gene alteration, low doses of DMBA are strongly cocarcinogenic. Using a transgenic model system, in which the p53 gene was deleted in the mammary gland, we examined the carcinogenic effects of a variety of external agents and internal factors given at either low doses or physiological doses. These agents/factors included DMBA, gamma-radiation, Brca2 heterozygosity, and steroid hormones. All agents/factors increased the tumorigenic response of the p53 null mammary cells, even under conditions where no tumorigenic response was observed in the p53 wildtype mammary cell. The strongest cocarcinogenic effect was observed with the steroid hormone progesterone. The majority of tumors were highly aneuploid and composed of nuclear igh-grade cells. The mechanism for the aneuploidy and secondary events associated with high tumorigenicity were examined using array technology. These results demonstrate that, on a background of underlying genetic instability, very low doses of environmental mutagens and mitogens can produce strong cocarcinogenic effects.
Medina
Daniel
D
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Ullrich
Robert
R
Meyn
Raymond
R
Wiseman
Roger
R
Donehower
Larry
L
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D024682:BRCA2 Protein / Q000378:metabolism; D002274:Carcinogens, Environmental / Q000633:toxicity*; D005260:Female; D016158:Genes, p53 / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011374:Progesterone / Q000009:adverse effects / Q000494:pharmacology / Q000633:toxicity; D011829:Radiation Dosage
D024682:BRCA2 Protein; D002274:Carcinogens, Environmental; D011374:Progesterone; D015127:9,10-Dimethyl-1,2-benzanthracene