Carcinogenesis, Vol. 22, No. 9, 1573-1576,
September 2001
© 2001 Oxford University Press
SHORT COMMUNICATION |
Catechol estrogen metabolites and conjugates in mammary tumors and hyperplastic tissue from estrogen receptor-
knock-out (ERKO)/Wnt-1 mice: implications for initiation of mammary tumors
1 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6085,
2 Division of Hematology, Oncology and Endocrinology, Cancer Center, University of Virginia Health Science Center, Charlottesville, VA 22908 and
3 Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
A novel model of breast cancer was established by crossing mice carrying the Wnt-1 transgene (100% of adult females develop spontaneous mammary tumors) with the ERKO mouse line, in which mammary tumors develop despite a lack of functional estrogen receptor-
. To begin investigating whether metabolite-mediated genotoxicity of estrogens may play an important role in the initiation of mammary tumors, the pattern of estrogen metabolites and conjugates was examined in ERKO/Wnt-1 mice. Extracts of hyperplastic mammary tissue and mammary tumors were analyzed by HPLC with identification and quantification of compounds by multichannel electrochemical detection. Picomole amounts of the 4-catechol estrogens (CE) were detected, but their methoxy conjugates, as well as the 2-CE and their methoxy conjugates, were not. 4-CE conjugates with glutathione or its hydrolytic products (cysteine and N-acetylcysteine) were detected in picomole amounts in both tumors and hyperplastic mammary tissue, demonstrating the formation of CE-3,4-quinones. These preliminary findings show that the estrogen metabolite profile in the mammary tissue is unbalanced, in that the normally minor 4-CE metabolites were detected in the mammary tissue and not the normally predominant 2-CE. These results are consistent with the hypothesis that the mammary tumor development is primarily initiated by metabolism of estrogens to 4-CE and, then, to CE-3,4-quinones, which may react with DNA to induce oncogenic mutations.
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