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

The Apc(Min/+) (Min) mouse is genetically predisposed to both intestinal and mammary tumorigenesis. We investigated age-related changes in the susceptibility of mice (before, during and after puberty) 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 killed humanely at 18 weeks of age. Min mice irradiated at 7-10 weeks of age (after puberty) developed mammary tumors with squamous metaplasia, whereas their wild-type littermates did not. Interestingly, irradiation of Min mice at 2-5 weeks (before and during puberty, respectively) 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 after puberty 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 4 groups: control, g gamma-irradiated (2 Gy), MNU-treated (40 mg/kg, i.p.) and combined treatment of radiation with subsequent MNU after 3 days. Rats with palpable tumors were sacrificed at 50 weeks of age to collect tumors for histologic 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 nonmutated, 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 g gamma-ray- and combined treatment-induced cancers than in MNU-induced cancers. These results indicate that combined exposure to the 2 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.