Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesis

Daniel Medina, Robert Ullrich, Raymond Meyn, Roger Wiseman, Larry Donehower

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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, γ-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.

Original languageEnglish (US)
Pages (from-to)178-183
Number of pages6
JournalEnvironmental and Molecular Mutagenesis
Volume39
Issue number2-3
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Environmental Carcinogens
9,10-Dimethyl-1,2-benzanthracene
p53 Genes
carcinogen
Tumor Suppressor Genes
tumor
Transgenic Mice
Tumors
Carcinogenesis
Breast
Genes
Steroid hormones
Steroids
Aneuploidy
Hormones
Carcinogens
gene
Modifier Genes
Radiation
steroid

Keywords

  • Environmental agents
  • Hormones
  • Mammary
  • P53

ASJC Scopus subject areas

  • Environmental Science(all)
  • Environmental Chemistry
  • Genetics
  • Genetics(clinical)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesis. / Medina, Daniel; Ullrich, Robert; Meyn, Raymond; Wiseman, Roger; Donehower, Larry.

In: Environmental and Molecular Mutagenesis, Vol. 39, No. 2-3, 2002, p. 178-183.

Research output: Contribution to journalArticle

Medina, Daniel ; Ullrich, Robert ; Meyn, Raymond ; Wiseman, Roger ; Donehower, Larry. / Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesis. In: Environmental and Molecular Mutagenesis. 2002 ; Vol. 39, No. 2-3. pp. 178-183.
@article{0150505bb34e4903801e3e0d48860b9c,
title = "Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesis",
abstract = "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, γ-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.",
keywords = "Environmental agents, Hormones, Mammary, P53",
author = "Daniel Medina and Robert Ullrich and Raymond Meyn and Roger Wiseman and Larry Donehower",
year = "2002",
doi = "10.1002/em.10064",
language = "English (US)",
volume = "39",
pages = "178--183",
journal = "Environmental and Molecular Mutagenesis",
issn = "0893-6692",
publisher = "Wiley-Liss Inc.",
number = "2-3",

}

TY - JOUR

T1 - Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesis

AU - Medina, Daniel

AU - Ullrich, Robert

AU - Meyn, Raymond

AU - Wiseman, Roger

AU - Donehower, Larry

PY - 2002

Y1 - 2002

N2 - 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, γ-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.

AB - 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, γ-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.

KW - Environmental agents

KW - Hormones

KW - Mammary

KW - P53

UR - http://www.scopus.com/inward/record.url?scp=0036208294&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036208294&partnerID=8YFLogxK

U2 - 10.1002/em.10064

DO - 10.1002/em.10064

M3 - Article

C2 - 11921187

AN - SCOPUS:0036208294

VL - 39

SP - 178

EP - 183

JO - Environmental and Molecular Mutagenesis

JF - Environmental and Molecular Mutagenesis

SN - 0893-6692

IS - 2-3

ER -