Characterization of murine cell lines from Diethylstilbestrol-Induced uterine endometrial Adenocarcinomas |
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Authors: | Charles D Hébert Sumiyo Endo Kenneth S Korach Jeff Boyd J Carl Barrett John A Mclachlan Retha R Newbold |
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Institution: | (1) Laboratory of Reproductive and Developmental Toxicology (C. D. H., S, E., K. S. K., J. A. M., R. R. N.), Division of Intramural Research, National Institute of Environmental Health Sciences, 27709 Research Triangle Park, North Carolina;(2) Laboratory of Molecular Carcinogenesis (J. B., J. C. B.), Division of Intramural Research, National Institute of Environmental Health Sciences, 27709 Research Triangle Park, North Carolina |
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Abstract: | Neonatal treatment with estrogens is associated with development of uterine adenocarcinomas in CD-1 mice. Treatment with the
synthetic estrogen diethylstilbestrol (DES) on Days 1 to 5 after birth results in 90% incidence of these hormonedependent
lesions in 18-mo.-old mice. Three cell lines were established from these DES-associated tumors. Each of these cell lines exhibited
morphologic and ultrastructural characteristics of transformed epithelial cells, including an increased nuclear:ytoplasmic
ratio, enlarged and irregular nuclei with multiple nucleoli and areas of chromatin condensation, positive staining for cytokeratin,
desmosomes, and microvilli. After subcutaneous injection into nude mice, all three cell lines formed solid tumors within 4
wk. Although the primary uterine tumors and tumor transplants in nude mice had been shown to be estrogen-dependent and estrogen-receptor
positive, neither the monolayer growth nor the tumorigenicity of any of the three cell lines in this study was enhanced by
or dependent on estrogen. Estrogen receptor levels were low in early and intermediate passage cells. Allele-specific oligonucleotide
hybridization analysis of PCR-amplified cell line DNA revealed no point mutations in the 12th, 13th, or 61st codons of the
K-ras or H-ras protooncogenes. Southern analysis revealed no changes in genomic organization of the putative tumor suppressor
gene DCC, but demonstrated a three-to four-fold amplification of the c-myc gene in one cell line. Expression of c-myc RNA
was concomitantly increased in the same cell line. These three transformed cell lines represent the end point in the process
of hormone-associated tumorigenesis and as such should prove useful in investigating the molecular changes and the mechanisms
involved in hormonal carcinogenesis. |
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Keywords: | uterine adenocarcinoma diethylstilbestrol hormonal carcinogenesis |
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