Mammary tumorigenesis in ApcMin/+ mice is enhanced by X irradiation with a characteristic age dependence

The ApcMin/+ (Min) mouse is a genetically predisposed model of both intestinal and mammary tumorigenesis. We investigated age-related changes in the susceptibility to radiation-induced mammary tumorigenesis using this model. Female Min and wild-type mice having the C57BL/6J background were irradiated with 2 Gy of X-rays at 2, 5, 7 and 10 weeks and sacrificed at 18 weeks of age. Min mice irradiated at 7-10 weeks of age developed mammary tumors with squamous metaplasia, whereas their wild-type littermates did not. Interestingly, irradiation of Min mice at 2-5 weeks did not induce mammary tumors but rather cystic nodules with metaplasia. The mammary tumors exhibited increased nuclear beta-catenin protein and loss of the wild-type Apc allele. Our results show that susceptibility to radiation-induced mammary tumorigenesis increases with age in Min mice, suggesting that the tumorigenic effect of ionizing radiation targets the lobular-alveolar progenitor cells, which increase in number with age and are controlled by beta-catenin signaling

Cooperative induction of rat mammary cancer by radiation and 1-methyl-1-nitrosourea via the oncogenic pathways involving c-Myc activation and H-ras mutation

Humans are continually exposed to various environmental carcinogens. Cancers may arise as a result of exposure to carcinogenic chemicals, ionizing radiation or a combination thereof. However, the mechanism of combined carcinogenesis has been only deduced from oncogenic actions of individual agents. Here, we analyzed experimental mammary carcinogenesis caused by a combination of radiation and a chemical carcinogen, 1-methyl-1-nitrosourea (MNU). Seven-week-old female Sprague-Dawley rats were divided into four groups: control, gamma-irradiated (2 Gy), MNU-treated (40 mg/kg, i.p.), and combined treatment of radiation with subsequent MNU after three days. Rats with palpable tumors were sacrificed at 50 weeks of age to collect tumors for histological typing and mutational analysis of the H-ras gene codon 12. The combined treatment induced adenocarcinomas, but not fibroadenomas, more efficiently than radiation or MNU alone. The H-ras mutation was not seen in radiation-induced carcinomas and was specific to MNU-induced carcinomas in individually treated groups. In the combined treatment group, H-ras-mutated, but not non-mutated, tumors were more frequent and developed significantly earlier than in the MNU-treated group. Significantly higher numbers of cells were stained for activated c-Myc protein in -ray- and combined treatment-induced cancers than in MNU-induced cancers. These results indicate that combined exposure to the two carcinogens elicits an unexpected cooperativity in which pre-irradiation enhances mammary carcinogenesis predominantly through the oncogenic pathway involving H-ras, possibly by synergism with c-Myc activation