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

• Published in: Carcinogenesis (New York) 2001-09, Vol.22 (9), p.1573-1576
• Main Authors: Devanesan, Prabu, Santen, Richard J., Bocchinfuso, Wayne P., Korach, Kenneth S., Rogan, Eleanor G., Cavalieri, Ercole
• Format: Article
• Language: English
• Subjects: Animal tumors. Experimental tumors; Animals; Biological and medical sciences; catechol estrogen quinone(s); catechol estrogen(s); CE-Q; Crosses, Genetic; Cys; cysteine; ERKO; estradiol; estrogen receptor; Estrogen Receptor alpha; estrogen receptor-^a; estrogen receptor-α knock-out; Estrogens - metabolism; Estrogens, Catechol - metabolism; estrone; Experimental genital and mammary tumors; Female; glutathione; Glutathione - metabolism; glutathione moiety; GSH; hydroxyestradiol; hydroxyestrone; Hyperplasia - metabolism; Male; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Medical sciences; Mice; Mice, Knockout; Mice, Transgenic; N-acetylcysteine; NAcCys; OHE1; OHE2; Proto-Oncogene Proteins - genetics; Receptors, Estrogen - genetics; SG; Tumors; Wnt Proteins; Wnt1 Protein; Zebrafish Proteins
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/22.9.1573

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.