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, ␥-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. Environ. Mol. Mutagen. 39: 178-183, 2002.

The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans

“…As compared to Brca2 wild-type, Brca2 haploinsufficiency resulted in a modest increase in mammary tumor incidence in glands arising from p53 null transplanted mammary cells. A decrease in tumor latency was not observed (Medina et al, 2002).…”

“…Although the repair of ENU-damaged DNA, which produces DNA base modifications without DSBs, may not be a particularly suitable model in which to examine the effects of Brca1 haploinsufficiency. Medina et al (2002) employed a mammary transplant approach to examine the effects of p53 deficiency and Brca2 haploinsufficiency on tumor incidence and latency by transplantation of p53 null mammary cells on a BALB/c genetic background. As compared to Brca2 wild-type, Brca2 haploinsufficiency resulted in a modest increase in mammary tumor incidence in glands arising from p53 null transplanted mammary cells.…”

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

“…The phosphorylation status of p53 determines the stability of the protein and controls cell cycle progression, which serves as a master-switch for promoting apoptosis (Ginsberg et al, 1991;Ashcroft and Vousden, 1999;Colman et al, 2000;Asher et al, 2001;Sogame et al, 2003). Alterations of p53 protein, such as missense mutations and loss of its expression caused by nonsense or frame-shift mutations, can result in carcinogenesis (Hussain and Harris, 1998;Medina et al, 2002;Shirai et al, 2002;Nishikawa et al, 2003;Hofseth et al, 2004).…”

Ultraviolet irradiation-induced K+ channel activity involving p53 activation in corneal epithelial cells

“…The phosphorylation status of p53 determines the stability of the protein and controls cell cycle progression, which serves as a master-switch for promoting apoptosis (Ginsberg et al, 1991;Ashcroft and Vousden, 1999;Colman et al, 2000;Asher et al, 2001;Sogame et al, 2003). Alterations of p53 protein, such as missense mutations and loss of its expression caused by nonsense or frame-shift mutations, can result in carcinogenesis (Hussain and Harris, 1998;Medina et al, 2002;Shirai et al, 2002;Nishikawa et al, 2003;Hofseth et al, 2004). In some cases, p53 becomes a molecular signature based on the type of cancer (Hussain et al, 2000).…”