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, Ercole Cavalieri

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1573-1576
Number of pages4
JournalCarcinogenesis
Volume22
Issue number9
StatePublished - Oct 8 2001

ASJC Scopus subject areas

  • Cancer Research

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