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

• Published in: International journal of cancer 2005-06, Vol.115 (2), p.187-193
• Main Authors: Imaoka, Tatsuhiko, Nishimura, Mayumi, Teramoto, Ayako, Nishimura, Yukiko, Ootawara, Masami, Osada, Harumi, Kakinuma, Shizuko, Maekawa, Akihiko, Shimada, Yoshiya
• Format: Article
• Language: English
• Subjects: 1‐methyl‐1‐nitrosourea; Adenocarcinoma - etiology; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Alkylating Agents - toxicity; Animals; Biological and medical sciences; carcinogenesis; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Cocarcinogenesis; combined exposure; Female; Fibroadenoma - etiology; Fibroadenoma - pathology; Gamma Rays; Genes, ras - genetics; Humans; H‐ras; Incidence; ionizing radiation; mammary cancer; Mammary Neoplasms, Experimental - etiology; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Medical sciences; Methylnitrosourea - toxicity; mutation; Mutation - genetics; Physical agents; Proto-Oncogene Proteins c-myc - metabolism; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Signal Transduction; Survival Rate; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.20904

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, gγ‐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 gγ‐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.