Journal Article

Catechol estrogen metabolites and conjugates in mammary tumors and hyperplastic tissue from estrogen receptor-α knock-out (ERKO)/Wnt-1 mice: implications for initiation of mammary tumors

Prabu Devanesan, Richard J. Santen, Wayne P. Bocchinfuso, Kenneth S. Korach, Eleanor G. Rogan and Ercole Cavalieri

in Carcinogenesis

Volume 22, issue 9, pages 1573-1576
Published in print September 2001 | ISSN: 0143-3334
Published online September 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.9.1573
Catechol estrogen metabolites and conjugates in mammary tumors and hyperplastic tissue from estrogen receptor-α knock-out (ERKO)/Wnt-1 mice: implications for initiation of mammary tumors

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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-α. 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.

Keywords: CE, catechol estrogen(s); CE-Q, catechol estrogen quinone(s); Cys, cysteine; E1, estrone; E2, estradiol; ER, estrogen receptor; ERKO, estrogen receptor-α knock-out; GSH, glutathione; NAcCys, N-acetylcysteine; OHE1, hydroxyestrone; OHE2, hydroxyestradiol; -SG, glutathione moiety

Journal Article.  2603 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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