Catechol estrogen metabolites and conjugates in mammary tumors and hyperplastic tissue from estrogen receptor-alpha knock-out (ERKO)/Wnt-1 mice: implications for initiation of mammary tumors
P. Devanesan et al., Catechol estrogen metabolites and conjugates in mammary tumors and hyperplastic tissue from estrogen receptor-alpha knock-out (ERKO)/Wnt-1 mice: implications for initiation of mammary tumors, CARCINOGENE, 22(9), 2001, pp. 1573-1576
A novel model of breast cancer was established by crossing mice carrying th
e 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-alpha. To begin investigating whether metab
olite-mediated genotoxicity of estrogens may play an important role in the
initiation of mammary tumors, the pattern of estrogen metabolites and conju
gates was examined in ERKO/Wnt-1 mice. Extracts of hyperplastic mammary tis
sue and mammary tumors were analyzed by HPLC with identification and quanti
fication of compounds by multichannel electrochemical detection. Picomole a
mounts of the 4-catechol estrogens (CE) were detected, but their methoxy co
njugates, as well as the 2-CE and their methoxy conjugates, were not. 4-CE
conjugates with glutathione or its hydrolytic products (cysteine and N-acet
ylcysteine) were detected in picomole amounts in both tumors and hyperplast
ic mammary tissue, demonstrating the formation of CE-3,4-quinones. These pr
eliminary findings show that the estrogen metabolite profile in the mammary
tissue is unbalanced, in that the normally minor 4-CE metabolites were det
ected in the mammary tissue and not the normally predominant 2-CE. These re
sults 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.