The overall objective of this proposal is to demonstrate at the molecular level the exciting and novel idea that estrogens are involved in the causation of breast and prostate cancer via a unifying mechanism that involves oxidation of endogenous 4-catechol estrogen (CE) metabolites to CE-3,4-quinones (CE-3, 4-Q) and reaction of these electrophiles with DNA. Formation of depurinating adducts that generate apurinic sites in DNA would be the critical event leading to oncogenic mutations that initiate breast and prostate cancer. To gain new, substantial evidence that the 4-CE oxidative pathway is the critical initiating event, we plan to investigate the fate of 17beta-estradiol (E2) and estrone (E1) in Syrian golden hamsters and Noble rats in relation to the induction of kidney and prostate tumors, respectively. Our approach is to identify and quantify estrogen metabolites, including CE, depurinating CE-DNA adducts, and CE-glutathione (GSH) and methoxyCE conjugates into which E1 and E2 are converted in these animals models. We will also analyze breast, prostrate and urine samples from human subjects with and without cancer. The altered amounts and altered ratios of these compounds will provide evidence on the key events leading to estrogen-induced tumor initiation. These objectives will be achieved by the following specific aims: (1) Identify and quantify the depurinating DNA adducts [4- OHE1(E2)-1-N7Gua and 4-OHE1(E2)-1-N3Ade] in the kidney and urine of male Syrian golden hamsters and the prostate of Noble rats treated with E2 at various dose levels, and compare the results with those from hamsters and rats treated with E2 plus: (a) buthionine sulfoximine (inhibitor of the synthesis of the protective GSH), (b) Ro41-0960 (competitor for the protective catechol-O-methyltransferase), (c) dicoumarol (inhibitor of the protective quinone oxidoreductase) or (d) alpha-naphthoflavone (inhibitor of cytochrome P450 1). (2) Identify and quantify the major estrogen metabolites, CE conjugates and CE adducts in human breast, prostate and urine samples obtained from subjects with and without breast or prostate cancer. From these studies, we expect to demonstrate that the pathway of oxidation of 4-CE to CE-3,4-Q and their binding to DNA to form depurinating adducts is the critical event in the initiation of breast and prostate cancer. In turn, this research will identify biomarkers that will be useful in determining cancer risk in humans.
| Cavalieri, Ercole; Saeed, Muhammad; Zahid, Muhammad et al. (2012) Mechanism of DNA depurination by carcinogens in relation to cancer initiation. IUBMB Life 64:169-79 |
| Zahid, Muhammad; Saeed, Muhammad; Rogan, Eleanor G et al. (2010) Benzene and dopamine catechol quinones could initiate cancer or neurogenic disease. Free Radic Biol Med 48:318-24 |
| Saeed, Muhammad; Rogan, Eleanor; Cavalieri, Ercole (2009) Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol: the defining link to natural estrogens. Int J Cancer 124:1276-84 |
| Saeed, Muhammad; Higginbotham, Sheila; Gaikwad, Nilesh et al. (2009) Depurinating naphthalene-DNA adducts in mouse skin related to cancer initiation. Free Radic Biol Med 47:1075-81 |
| Lu, Fang; Zahid, Muhammad; Wang, Cheng et al. (2008) Resveratrol prevents estrogen-DNA adduct formation and neoplastic transformation in MCF-10F cells. Cancer Prev Res (Phila Pa) 1:135-45 |
| Gaikwad, Nilesh W; Yang, Li; Muti, Paola et al. (2008) The molecular etiology of breast cancer: evidence from biomarkers of risk. Int J Cancer 122:1949-57 |
| Chakravarti, Dhrubajyoti; Venugopal, Divya; Mailander, Paula C et al. (2008) The role of polycyclic aromatic hydrocarbon-DNA adducts in inducing mutations in mouse skin. Mutat Res 649:161-78 |
| Zahid, Muhammad; Saeed, Muhammad; Lu, Fang et al. (2007) Inhibition of catechol-O-methyltransferase increases estrogen-DNA adduct formation. Free Radic Biol Med 43:1534-40 |
| Gaikwad, Nilesh W; Rogan, Eleanor G; Cavalieri, Ercole L (2007) Evidence from ESI-MS for NQO1-catalyzed reduction of estrogen ortho-quinones. Free Radic Biol Med 43:1289-98 |
| Zahid, Muhammad; Gaikwad, Nilesh W; Rogan, Eleanor G et al. (2007) Inhibition of depurinating estrogen-DNA adduct formation by natural compounds. Chem Res Toxicol 20:1947-53 |
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