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.
Imaoka
Tatsuhiko
T
Research Center for Radiation Safety, National Institute of Radiological Sciences, Anagawa, Chiba, Japan.
Nishimura
Mayumi
M
Teramoto
Ayako
A
Nishimura
Yukiko
Y
Ootawara
Masami
M
Osada
Harumi
H
Kakinuma
Shizuko
S
Maekawa
Akihiko
A
Shimada
Yoshiya
Y
D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D003043:Cocarcinogenesis; D005260:Female; D018226:Fibroadenoma / Q000209:etiology / Q000473:pathology; D005720:Gamma Rays; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D015994:Incidence; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008770:Methylnitrosourea / Q000633:toxicity; D009154:Mutation / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015996:Survival Rate
D000477:Alkylating Agents; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D008770:Methylnitrosourea