Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators

E. L. Cavalieri, D. E. Stack, P. D. Devanesan, R. Todorovic, I. Dwivedy, S. Higginbotham, S. L. Johansson, K. D. Patil, M. L. Gross, J. K. Gooden, R. Ramanathan, R. L. Cerny, E. G. Rogan

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695 Scopus citations


Cancer is a disease that begins with mutation of critical genes: oncogenes and tumor suppressor genes. Our research on carcinogenic aromatic hydrocarbons indicates that depurinating hydrocarbon-DNA adducts generate oncogenic mutations found in mouse skin papillomas (Proc. Natl. Acad. Sci. USA 92:10422,1995). These mutations arise by mis-replication of unrepaired apurinic sites derived from the loss of depurinating adducts. This relationship led us to postulate that oxidation of the carcinogenic 4- hydroxy catechol estrogens (CE) of estrone (E1) and estradiol (E2) to catechol estrogen-3,4-quinones (CE-3, 4-Q) results in electrophilic intermediates that covalently bind to DNA to form depurinating adducts. The resultant apurinic sites in critical genes can generate mutations that may initiate various human cancers. The noncarcinogenic 2-hydroxy CE are oxidized to CE-2,3-Q and form only stable DNA adducts. As reported here, the CE-3,4-Q were bound to DNA in vitro to form the depurinating adduct 4-OHE1(E2)- 1(α,β)-N7Gua at 59-213 μmol/mol DNA-phosphate whereas the level of stable adducts was 0.1 μmol/mol DNA-phosphate. In female Sprague-Dawley rats treated by intramammillary injection of E2-3,4-Q (200 nmol) at four mammary glands, the mammary tissue contained 2.3 μmol 4-OHE2-1(αβ)-N7Gua/molDNA- phosphate. When 4-OHE1 (E2) were activated by horseradish peroxidase, lactoperoxidase, or cytochrome P450, 87-440 μmol of 4-OHE1(E2)-1(α,β)- N7Gua was formed. After treatment with 4-OHE2, rat mammary tissue contained 1.4 μmol of adduct/mol DNA-phosphate. In each case, the level of stable adducts was negligible. These results, complemented by other data, strongly support the hypothesis that CE-3,4-Q are endogenous tumor initiators.

Original languageEnglish (US)
Pages (from-to)10937-10942
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number20
StatePublished - Sep 30 1997

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