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

Abstract

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, γ-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 γ-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. © 2005 Wiley-Liss, Inc.