Frequent p53 and H-ras mutations in benzene- and ethylene oxide-induced mammary gland carcinomas from B6C3F1 mice.
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.
Houle
Christopher D
CD
Laboratory of Experimental Pathology, Research Triangle Park, North Carolina 27709, USA. houle@niehs.nih.gov
Ton
Thai-Vu T
TV
Clayton
Natasha
N
Huff
James
J
Hong
Hue-Hua L
HH
Sills
Robert C
RC
D000818:Animals; D001554:Benzene; D002273:Carcinogens; D003062:Codon; D004252:DNA Mutational Analysis; D005027:Ethylene Oxide; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D007150:Immunohistochemistry; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009154:Mutation; D016133:Polymerase Chain Reaction; D012376:Rodent Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D002273:Carcinogens; D003062:Codon; D016159:Tumor Suppressor Protein p53; D001554:Benzene; D005027:Ethylene Oxide