title: Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators.
abstract: 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(alpha,beta)-N7Gua at 59-213 micromol/mol DNA-phosphate whereas the level of stable adducts was 0.1 micromol/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 micromol 4-OHE2-1(alpha, beta)-N7Gua/molDNA-phosphate. When 4-OHE1(E2) were activated by horseradish peroxidase, lactoperoxidase, or cytochrome P450, 87-440 micromol of 4-OHE1(E2)-1(alpha, beta)-N7Gua was formed. After treatment with 4-OHE2, rat mammary tissue contained 1.4 micromol 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.
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805, USA. ecavalie@unmc.edu
authors.forename: E L
authors.initials: EL
authors.lastname: Cavalieri
authors.forename: D E
authors.initials: DE
authors.lastname: Stack
authors.forename: P D
authors.initials: PD
authors.lastname: Devanesan
authors.forename: R
authors.initials: R
authors.lastname: Todorovic
authors.forename: I
authors.initials: I
authors.lastname: Dwivedy
authors.forename: S
authors.initials: S
authors.lastname: Higginbotham
authors.forename: S L
authors.initials: SL
authors.lastname: Johansson
authors.forename: K D
authors.initials: KD
authors.lastname: Patil
authors.forename: M L
authors.initials: ML
authors.lastname: Gross
authors.forename: J K
authors.initials: JK
authors.lastname: Gooden
authors.forename: R
authors.initials: R
authors.lastname: Ramanathan
authors.forename: R L
authors.initials: RL
authors.lastname: Cerny
authors.forename: E G
authors.initials: EG
authors.lastname: Rogan
mesh_terms: D000818:Animals; D002273:Carcinogens; D006224:Cricetinae; D002393:Estrogens, Catechol / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008647:Mesocricetus; D051379:Mice; D009369:Neoplasms / Q000209:etiology*; D010084:Oxidation-Reduction; D011809:Quinones / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D002273:Carcinogens; D002393:Estrogens, Catechol; D011809:Quinones