{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T10:17:07Z","timestamp":1792059427812,"version":"4.4.0"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"20","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1997,9,30]]},"abstract":"<jats:p>\n                    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\u2013DNA adducts generate oncogenic mutations found in mouse skin papillomas (\n                    <jats:italic>Proc. Natl. Acad. Sci. USA<\/jats:italic>\n                    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 (E\n                    <jats:sub>1<\/jats:sub>\n                    ) and estradiol (E\n                    <jats:sub>2<\/jats:sub>\n                    ) 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\n                    <jats:italic>in vitro<\/jats:italic>\n                    to form the depurinating adduct 4-OHE\n                    <jats:sub>1<\/jats:sub>\n                    (E\n                    <jats:sub>2<\/jats:sub>\n                    )-1(\u03b1,\u03b2)-N7Gua at 59\u2013213 \u03bcmol\/mol DNA\u2013phosphate whereas the level of stable adducts was 0.1 \u03bcmol\/mol DNA\u2013phosphate. In female Sprague\u2013Dawley rats treated by intramammillary injection of E\n                    <jats:sub>2<\/jats:sub>\n                    -3,4-Q (200 nmol) at four mammary glands, the mammary tissue contained 2.3 \u03bcmol 4-OHE\n                    <jats:sub>2<\/jats:sub>\n                    -1(\u03b1,\u03b2)-N7Gua\/molDNA\u2013phosphate. When 4-OHE\n                    <jats:sub>1<\/jats:sub>\n                    (E\n                    <jats:sub>2<\/jats:sub>\n                    ) were activated by horseradish peroxidase, lactoperoxidase, or cytochrome P450, 87\u2013440 \u03bcmol of 4-OHE\n                    <jats:sub>1<\/jats:sub>\n                    (E\n                    <jats:sub>2<\/jats:sub>\n                    )-1(\u03b1, \u03b2)-N7Gua was formed. After treatment with 4-OHE\n                    <jats:sub>2<\/jats:sub>\n                    , rat mammary tissue contained 1.4 \u03bcmol of adduct\/mol DNA\u2013phosphate. 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.94.20.10937","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:31:44Z","timestamp":1027679504000},"page":"10937-10942","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":552,"title":["Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor\u2009initiators"],"prefix":"10.1073","volume":"94","author":[{"given":"E. L.","family":"Cavalieri","sequence":"first","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. E.","family":"Stack","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. D.","family":"Devanesan","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Todorovic","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Dwivedy","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Higginbotham","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. L.","family":"Johansson","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. D.","family":"Patil","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. L.","family":"Gross","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. K.","family":"Gooden","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Ramanathan","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. L.","family":"Cerny","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. G.","family":"Rogan","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805; Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130; and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1997,9,30]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/scientificamerican0996-62"},{"key":"e_1_3_3_2_2","first-page":"559","volume":"30","author":"Miller J A","year":"1970","unstructured":"J A Miller Cancer Res 30, 559\u2013576 (1970).","journal-title":"Cancer Res"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19810515)47:10<2327::AID-CNCR2820471003>3.0.CO;2-Z"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.22.10422"},{"key":"e_1_3_3_5_2","volume-title":"The Handbook of Environmental Chemistry: PAHs and Related Compounds","author":"Cavalieri E","year":"1997","unstructured":"E Cavalieri, E Rogan The Handbook of Environmental Chemistry: PAHs and Related Compounds, ed A H Neilson (Springer, Heidelberg) 3, , in press. (1997)."},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0163-7258(92)90015-R"},{"key":"e_1_3_3_7_2","first-page":"7415","volume":"50","author":"Preston-Martin S","year":"1990","unstructured":"S Preston-Martin, M C Pike, R K Ross, P A Jones, B E Henderson Cancer Res 50, 7415\u20137421 (1990).","journal-title":"Cancer Res"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.9.3650"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/87.13.964"},{"key":"e_1_3_3_10_2","unstructured":"International Agency for Research on Cancer: Monographs on the Evaluation of Carcinogenic Risks to Humans (1979) 21 279\u2013362."},{"key":"e_1_3_3_11_2","unstructured":"International Agency for Research on Cancer: Monographs on the Evaluation of Carcinogenic Risks to Humans (1987) 7 Suppl. 272\u2013310."},{"key":"e_1_3_3_12_2","first-page":"1","volume":"1","author":"Kirkman H","year":"1959","unstructured":"H Kirkman Natl Cancer Inst Monogr 1, 1\u201359 (1959).","journal-title":"Natl Cancer Inst Monogr"},{"key":"e_1_3_3_13_2","first-page":"5200","volume":"43","author":"Li J J","year":"1983","unstructured":"J J Li, S A Li, J K Klicka, J A Parsons, L K T Lam Cancer Res 43, 5200\u20135204 (1983).","journal-title":"Cancer Res"},{"key":"e_1_3_3_14_2","doi-asserted-by":"crossref","unstructured":"Ball P. & Knuppen R. (1980) Acta Endocrinol. (Copenhagen) 93 Suppl. 232 1\u2013127.","DOI":"10.1530\/acta.0.0930001-b"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0163-7258(93)90057-K"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/tx00030a016"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/tx960002q"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-4731(86)90080-4"},{"key":"e_1_3_3_19_2","first-page":"1858","volume":"46","author":"Li J J","year":"1987","unstructured":"J J Li, S A Li Fed Proc 46, 1858\u20131863 (1987).","journal-title":"Fed Proc"},{"key":"e_1_3_3_20_2","unstructured":"Byun J. Gooden J. Ramanathan R. Li K. Cavalieri E. & Gross M. L. (1997) J. Am. Soc. Mass Spectrom in press."},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0168-1176(93)03876-N"},{"key":"e_1_3_3_22_2","first-page":"112","volume-title":"Statistical Methods in Medical Research","author":"Armitage P","year":"1994","unstructured":"P Armitage Statistical Methods in Medical Research (Blackwell Scientific, Oxford), pp. 112 (1994)."},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(86)90128-0"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/tx00011a008"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197104222841604"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-2797(85)80125-3"},{"key":"e_1_3_3_27_2","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1007\/978-1-4757-0674-1_65","volume":"136","author":"Metzler M","year":"1981","unstructured":"M Metzler, J A McLachlan Adv Exp Med Biol 136A, 829\u2013837 (1981).","journal-title":"Adv Exp Med Biol"},{"key":"e_1_3_3_28_2","first-page":"120","volume":"37","author":"Jan S T","year":"1996","unstructured":"S T Jan, P D Devanesan, E G Rogan, E L Cavalieri Proc Am Assoc Cancer Res 37, 120 (1996).","journal-title":"Proc Am Assoc Cancer Res"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.36.040196.001223"},{"key":"e_1_3_3_30_2","first-page":"655","volume":"131","author":"Weisz J","year":"1992","unstructured":"J Weisz, Q D Bui, D Roy, J G Liehr Endocrinology 131, 655\u2013661 (1992).","journal-title":"Endocrinology"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.135.5.7956900"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1159\/000138406"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-4731(88)90288-9"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.20.9220"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.8.3294"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/0039-128X(92)90097-S"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)36551-1"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.18.9776"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/0960-0760(94)90037-X"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/16.6.1319"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)75968-7"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/0891-5849(90)90108-U"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/16.8.1941"},{"key":"e_1_3_3_44_2","first-page":"5515","volume":"54","author":"Han X","year":"1994","unstructured":"X Han, J G Liehr Carcinogenesis 54, 5515\u20135517 (1994).","journal-title":"Carcinogenesis"},{"key":"e_1_3_3_45_2","first-page":"23","volume":"7","author":"Nutter L M","year":"1991","unstructured":"L M Nutter, E O Ngo, Y J Abul-Hajj J Biol Chem 7, 23\u201328 (1991).","journal-title":"J Biol Chem"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1021\/tx00037a004"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19930515)71:10<3036::AID-CNCR2820711025>3.0.CO;2-P"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.1.259"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.94.20.10937","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T14:59:28Z","timestamp":1649861968000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.94.20.10937"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,9,30]]},"references-count":48,"journal-issue":{"issue":"20","published-print":{"date-parts":[[1997,9,30]]}},"alternative-id":["10.1073\/pnas.94.20.10937"],"URL":"https:\/\/doi.org\/10.1073\/pnas.94.20.10937","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,9,30]]},"assertion":[{"value":"1997-06-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"1997-07-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"1997-09-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}