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Predominant p53 GA Transition Mutation and Enhanced Cell Proliferation in Uterine Sarcomas of CBA Mice Treated with 1,2-Dimethylhydrazine

Cancer Research Centre, Russian Academy of Medical Sciences, Moscow, Russia

Hue-Hua L. Hong

Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Robert C. Sills

Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Alicia D. Bowser

Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Beth Gaul

Experimental Pathology Laboratories, Inc., Research Triangle Park, North Carolina 27709, USA

Gary A. Boorman

Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Vladimir S. Turusov

Cancer Research Centre, Russian Academy of Medical Sciences, Moscow, Russia

Theodora R. Devereux

Environmental Carcinogenesis Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Darlene Dixon

Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Mouse uterine tumors were examined for genetic alterations in the ras proto-oncogene and p⁵³ tumor suppressor gene arid for other biologically relevant immunohistochemical markers that may increase our understanding of the events that occur in uterine cancer. Fourteen dimethylhydrazine (DMH)-induced uterine sarcomas, including 3 primary malignant fibrous histiocytomas (MFH), 7 transplanted MFH, 3 stromal sarcomas, and 1 undifferentiated sarcoma, were first screened by immunohistochemistry for p53 missense mutations, followed by single strand conformation polymorphism analysis and DNA sequencing for the identification of point mutations. There was 100% correlation between p⁵³ protein immunopositivity and subsequent detection ofp53 mutations in DMH-induced malignant fibrous histiocytomas. All MFH had a characteristic p⁵³ G:CA:T transition mutation, consistent with O⁶-methylguanine mispairing with thymine, the most common DNA lesion caused by alkylating agents. DMH-induced uterine MFH with p⁵³ mutations also had a higher proliferative rate (qualitatively evaluated by immunohistochemical detection of proliferating cell nuclear antigen) when compared with other DMH-induced sarcomas. Uterine sarcomas were further evaluated for biological end points, such as estrogen receptor and desmin. Neoplastic cells from stromal sarcomas (SS), undifferentiated sarcomas (US), and MFH did not stain for desmin. The estrogen receptor was detected in normal uteri and a small portion of MFH, SS, and US. Our data suggest that DMH-induced uterine sarcomas are not consistent with smooth muscle cell origin and that a subset of these tumors, specifically DMH-induced malignant fibrous histiocytomas, have unique p⁵³ G:CA:T transitions and a high proliferative rate.

Key Words: Tumor suppressor gene • ras proto-oncogene • malignant fibrous histiocytoma • stromal sarcoma • undifferentiated sarcoma • estrogen receptor • desmin

Toxicologic Pathology, Vol. 26, No. 3, 367-374 (1998)
DOI: 10.1177/019262339802600310


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