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Frequent p53 and H-ras Mutations in Benzene- and Ethylene Oxide-Induced Mammary Gland Carcinomas from B6C3F1 Mice

¹ Experimental Pathology Laboratories, Inc., Research Triangle Park, North Carolina 27709, USA
² College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, USA
³ Laboratory of Experimental Pathology
^3,4 National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA

Correspondence: Address correspondence to: Christopher D. Houle, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA; e-mail:houle{at}niehs.nih.gov

Benzene and ethylene oxide are multisite carcinogens in rodents and classified as human carcinogens by the National Toxicology Program. In 2-year mouse studies, both chemicals induced mammary carcinomas. We examined spontaneous, benzene-, and ethylene oxide-induced mouse mammary carcinomas for p53 protein expression, using immunohistochemistry, and p53 (exons 5–8) and H-ras (codon 61) mutations using cycle sequencing techniques. p53 protein expression was detected in 42% (8/19) of spontaneous, 43% (6/14) of benzene-, and 67% (8/12) of ethylene oxide-induced carcinomas. However, semiquantitative evaluation of p53 protein expression revealed that benzene- and ethylene oxide-induced carcinomas exhibited expression levels five- to six-fold higher than spontaneous carcinomas. p53 mutations were found in 58% (7/12) of spontaneous, 57% (8/14) of benzene-, and 67% (8/12) of ethylene oxide-induced carcinomas. H-ras mutations were identified in 26% (5/19) of spontaneous, 50% (7/14) of benzene-, and 33% (4/12) of ethylene oxide-induced carcinomas. When H-ras mutations were present, concurrent p53 mutations were identified in 40% (2/5) of spontaneous, 71% (5/7) of benzene-, and 75% (3/4) of ethylene oxide-induced carcinomas. Our results demonstrate that p53 and H-ras mutations are relatively common in control and chemically induced mouse mammary carcinomas although both chemicals can alter the mutational spectra and more commonly induce concurrent mutations.

Key Words: p53 • H-ras • benzene • ethylene oxide • mammary gland carcinoma • mice • carcinogen

Abbreviations: EtO, ethylene oxide • PCR, polymerase chain reaction • AB, automation buffer • ROS, reactive oxygen species • DNA, deoxyribonucleic acid • IHC, immunohistochemistry • A, C, G, T, adenine, cytosine, guanine, thymine • NTP, National Toxicology Program

Toxicologic Pathology, Vol. 34, No. 6, 752-762 (2006)
DOI: 10.1080/01926230600935912


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