Depurinating estrogen-DNA adducts in the etiology and prevention of breast and other human cancers

Future Oncology

Volumn 6, Issue 1, 2010, Pages 75-91

  Cavalieri, Ercole L ^a   Rogan, Eleanor G ^a  

^a UNIVERSITY OF NEBRASKA MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLCYSTEINE; DNA; ESTRADIOL; ESTROGEN; ESTROGEN RECEPTOR; ESTROGEN RECEPTOR ALPHA; ESTRONE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE (PHOSPHATE) DEHYDROGENASE (QUINONE); RESVERATROL;

ANTIOXIDANT ACTIVITY; AUGUST COPENHAGEN IRISH RAT; BIG BLUE RAT; BREAST CANCER; CANCER PREVENTION; CARCINOGEN DNA INTERACTION; CARCINOGENESIS; CARCINOGENICITY; CELL TRANSFORMATION; DNA ADDUCT; DRUG STRUCTURE; EMBRYO CELL; ESTROGEN METABOLISM; ESTROGEN SYNTHESIS; GENOTOXICITY; HOMEOSTASIS; HUMAN; KNOCKOUT MOUSE; MUTAGENIC ACTIVITY; MUTAGENICITY; NONHODGKIN LYMPHOMA; NONHUMAN; PRIORITY JOURNAL; PROSTATE CANCER; RAT STRAIN; REVIEW; SENSITIVE TO CARCINOGENESIS MOUSE;

ACETYLCYSTEINE; ANIMALS; ANTINEOPLASTIC AGENTS; ANTIOXIDANTS; BREAST NEOPLASMS; DNA ADDUCTS; ESTROGENS; FEMALE; HUMANS; MALE; NEOPLASMS; STILBENES;

EID: 75149174413     PISSN: 14796694     EISSN: 17448301     Source Type: Journal    
DOI: 10.2217/fon.09.137     Document Type: Review

References (94)

1. Doll R. Peto R: The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Natl Cancer Inst. 66, 1191-1308 (1981).
2. IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans. IARC 29, 93-148 (1982).
3. Mehlman MA: Casual relationship between non-Hodgkin's lymphoma and exposure to benzene and benzene-containing solvents. Ann. NY Acad. Sci. 1076, 120-128 (2006).
4. Cavalieri E, Rogan E: Catechol quinones of estrogens in the initiation of breast, prostate, and other human cancers: keynote lecture. Ann. NY Acad. Sci. 1089, 286-301 (2006).
5. Li JJ, Li SA, Klicka JK, Parsons JA, Lam LK: Relative carcinogenic activity of various synthetic and natural estrogens in the Syrian hamster kidney. Cancer Res. 43, 5200-5204 (1983).
6. Liehr JG, Fang WF, Sirbasku DA, Ari-Ulubelen A: Carcinogenicity of catechol estrogens in syrian hamsters. J. Steroid Biochem. 24, 353-356 (1986).
7. Li JJ, Li SA: Estrogen carcinogenesis in Syrian hamster tissues: role of metabolism. Fed. Proc. 46, 1858-1863 (1987).
8. Newbold RR, Liehr JG: Induction of uterine adenocarcinoma in CD-1 mice by catechol estrogens. Cancer Res. 60, 235-237 (2000).
9. Nandi S: Role of hormones in mammary neoplasia. Cancer Res. 38, 4046-4049 (1978).
10. Li JJ: Estrogen carcinogenesis in hamster tissues: update. Endocr. Rev. 14, 94-95 (1993).
11. Lang R, Redmann U: Non-mutagenicity of some sex hormones in the Ames salmonella/microsome mutagenicity test. Mutat. Res. 67, 361-365 (1979).
12. Lang R, Reimann R: Studies for a genotoxic potential of some endogenous and exogenous sex steroids. I. Communication: examination for the induction of gene mutations using the Ames Salmonella/microsome test and the HGPRT test in V79 cells. Environ. Mol. Mutagen. 21, 272-304 (1993).
13. Drevon C, Piccoli C, Montesano R: Mutagenicity assays of estrogenic hormones in mammalian cells. Mutat. Res. 89, 83-90 (1981).
14. Feigelson HS, Henderson BE: Estrogens and breast cancer. Carcinogenesis 17, 2279-2284 (1996).
15. Dickson RB, Stancel GM: Estrogen receptor-mediated processes in normal and cancer cells. J. Natl. Cancer Inst. Monogr. 27, 135-145 (2000).
16. Furth J: Hormones as etiological agents in neoplasia. In: Cancer. A Comprehensive Treatise. 1. Etiology: Chemical and Physical Carcinogenesis. Becker FF (Ed.), Cancer Plenum Press, NY, USA, 4, 89-134 (1982).
17. Li JJ, Li SA: Estrogen carcinogenesis in hamster tissues: a critical review. Endocr. Rev. 11, 524-531 (1990).
18. Nandi S, Guzman RC, Yang J: Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis. Proc. Natl Acad. Sci. USA 92, 3650-3657 (1995).
19. Hahn WC, Weinberg RA: Rules for making human tumor cells. N. Engl. J. Med. 347, 1593-1603 (2002).
20. Miller JA: Carcinogenesis by chemicals: an overview - GHA Clowes memorial lecture. Cancer Res. 30, 559-576 (1970).
21. Miller EC, Miller JA: Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules. Cancer 47, 2327-2345 (1981).
22. Cavalieri EL, Stack DE, Devanesan PD et al.: Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc. Natl Acad. Sci. USA 94, 10937-10942 (1997).
23. Cavalieri E, Chakravarti D, Guttenplan J et al.: Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention. Biochim. Biophys. Acta 1766, 63-78 (2006). ■ Reviews the evidence until 2006 indicating that estrogens can become endogenous cancer initiators when catechol estrogen-3,4-quinones react with DNA to form specific depurinating adducts.
24. Saeed M, Rogan E, Cavalieri E: Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol: the defining link to natural estrogens. Int. J. Cancer 124, 1276-1284 (2009). ■■ The synthetic human carcinogen diethylstilbestrol and the natural estrogens estrone and estradiol have in common the metabolic formation of catechol quinones, which react with DNA to afford the depurinating N3Ade and N7Gua adducts.
25. Spink DC, Hayes CL, Young NE et al.: The effects of 2,3,7,8- tetrachlorodibenzo-p-dioxin on estrogen metabolism in MCF-7 breast cancer cells: evidence for induction of a novel 17 β-estradiol 4-hydroxylase. J. Steroid Biochem. Mol. Biol. 51, 251-258 (1994).
26. Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutter TR: 17β-estradiol hydroxylation catalyzed by human cytochrome P4501B1. Proc. Natl Acad. Sci. USA 93, 9776-9781 (1996).
27. Spink DC, Spink BC, Cao JQ et al.: Differential expression of CYP1A1 and CYP1B1 in human breast epithelial cells and breast tumor cells. Carcinogenesis 19, 291-298 (1998).
28. Männistö PT, Kaakkola S: Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol. Rev. 51, 593-628 (1999).
29. Mobley JA, Bhat AS, Brueggemeier RW: Measurement of oxidative DNA damage by catechol estrogens and analogues in vitro. Chem. Res. Toxicol. 12, 270-277 (1999).
30. Cavalieri E: Minisymposium on endogenous carcinogens: the catechol estrogen pathway. An introduction. Polycycl. Aromat. Compd 6, 223-228 (1994).
31. Zahid M, Kohli E, Saeed M, Rogan E, Cavalieri E: The greater reactivity of estradiol-3,4-quinone vs estradiol-2,3-quinone with DNA in the formation of depurinating adducts: implications for tumor-initiating activity. Chem. Res. Toxicol. 19, 164-172 (2006). ■■ The greater reactivity of estradiol-3,4-quinone versus estradiol-2,3-quinone with DNA to form depurinating adducts correlates with the carcinogenicity, mutagenicity and cell-transforming activity of their precursors, the catechol estrogens 4-hydroxyestradiol and 2-hydroxyestradiol.
32. Gaikwad NW, Rogan EG, Cavalieri EL: Evidence from ESI-MS for NQO1-catalyzed reduction of estrogen ortho-quinones. Free Radic. Biol. Med. 43, 1289-1298 (2007).
33. Talalay P, Dinkova-Kostova AT, HoltzclawWD: Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis. Adv. Enzyme Regul. 43, 121-134 (2003).
34. Stack DE, Byun J, Gross ML, Rogan EG, Cavalieri EL: Molecular characteristics of catechol estrogen quinones in reactions with deoxyribonucleosides. Chem. Res. Toxicol. 9, 851-859 (1996).
35. Li KM, Todorovic R, Devanesan P et al.: Metabolism and DNA binding studies of 4-hydroxyestradiol and estradiol-3,4-quinone in vitro and in female ACI rat mammary gland in vivo. Carcinogenesis 25, 289-297 (2004).
36. Cavalieri E, Rogan E: Mechanisms of tumor initiation by polycyclic aromatic hydrocarbons in mammals. In: The Handbook of Environmental Chemistry. PAHs and Related Compounds. Neilson AH (Ed.), Springer-Verlag, Heidelberg, Germany, 3J, 81-117 (1998).
37. Chakravarti D, Pelling JC, Cavalieri EL, Rogan EG: Relating aromatic hydrocarbon-induced DNA adducts and H-ras mutations in mouse skin papillomas: the role of apurinic sites. Proc. Natl Acad. Sci. USA 92, 10422-10426 (1995).
38. Jankowiak R, Rogan EG, Cavalieri EL: The role of fluorescence line-narrowing spectroscopy and related luminescence-based techniques in the elucidation of mechanisms of tumor initiation by polycyclic aromatic hydrocarbons and estrogens. J. Phys. Chem. B 108, 10266-10283 (2004).
39. Devanesan PD, RamaKrishna NVS, Padmavathi NS et al.: Identification and quantitation of 7,12-dimethylbenz[a]anthracene-DNA adducts formed in mouse skin. Chem. Res. Toxicol. 6, 364-371 (1993).
40. Cavalieri EL, Rogan EG, Li KM et al.: Identification and quantification of the depurinating DNA adducts formed in mouse skin treated with dibenzo[a,l]pyrene (DB[a,l]P), or its metabolites and in rat mammary gland treated with DB[a,l]P. Chem. Res. Toxicol. 18, 976-983 (2005).
41. Todorovic R, Devanesan P, Rogan E, CavalieriE: Identification and quantification of stable DNA adducts of dibenzo[a,l]pyrene or its metabolites in vitro, and in mouse skin and rat mammary gland. Chem. Res. Toxicol. 18, 984-990 (2005).
42. Rogan EG, Devanesan PD, RamaKrishna NV et al.: Identification and quantitation of benzo[a]pyrene-DNA adducts formed in mouse skin. Chem. Res. Toxicol. 6, 356-363 (1993).
43. Chakravarti D, Mailander P, Li KM et al.: Evidence that a burst of DNA depurination in SENCAR mouse skin induces error-prone repair and forms mutations in the H-ras gene. Oncogene 20, 7945-7953 (2001). ■ Treatment of SENCAR mouse skin with estradiol-3,4-quinone produces A to G mutations in the H-ras gene after 6h to 3 days. These results confirm the genotoxic effects of catechol estrogen quinones.
44. Mailander PC, Meza JL, Higginbotham S, Chakravarti D: Induction of A.T to G.C mutations by erroneous repair of depurinated DNA following estrogen treatment of the mammary gland of ACI rats. J. Steroid Biochem. Mol. Biol. 101, 204-215 (2006).
45. Miller WR, O'Neill J: The importance of local synthesis of estrogen within the breast. Steroids 50, 537-548 (1987).
46. Simpson ER, Mahendroo MS, Means GD et al.: Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr. Rev. 15, 342-355 (1994).
47. Jefcoate CR, Liehr JG, Santen RJ et al.: Tissue-specific synthesis and oxidative metabolism of estrogens. J. Natl. Cancer Inst. Monogr. 27, 95-112 (2000).
48. Pasqualini JR, Chetrite G, Blacker C et al.: Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients. J. Clin. Endocrinol. Metab. 81, 1460-1464 (1996).
49. Chetrite GS, Cortes-Prieto J, Philippe JC, Wright F, Pasqualini JR: Comparison of estrogen concentrations, estrone sulfatase and aromatase activities in normal, and in cancerous, human breast tissues. J. Steroid Biochem. Mol. Biol. 72, 23-27 (2000).
50. Lu F, Zahid M, Saeed M, Cavalieri EL, Rogan EG: Estrogen metabolism and formation of estrogen-DNA adducts in estradiol-treated MCF-10F cells. The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin induction and catechol-O-methyltransferase inhibition. J. Steroid Biochem. Mol. Biol. 105, 150-158 (2007).
51. Paracchini V, Raimondi S, Gram IT et al.: Meta- and pooled analyses of the cytochrome P-450 1B1 Val432Leu polymorphism and breast cancer: a HuGE-GSEC review. Am. J. Epidemiol. 165, 115-125 (2006).
52. Mitrunen K, Hirvonen A: Molecular epidemiology of sporadic breast cancer. The role of polymorphic genes involved in oestrogen biosynthesis and metabolism. Mutat. Res. 544, 9-41 (2003).
53. Singh S, Zahid M, Saeed M et al.: NAD(P)H:quinone oxidoreductase 1 Arg139Trp and Pro187Ser polymorphism imbalance estrogen metabolism towards DNA adduct formation in human mammary epithelial cells. J. Steroid Biochem. Mol. Biol. 117, 56-66 (2009).
54. Ross D, Kepa JK, Winski SL, Beall HD, Anwar A, Siegel D: NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem. Biol. Interact. 129, 77-97 (2000).
55. Dawling S, Roodi N, Parl FF: Methoxyestrogens exert feedback inhibition on cytochrome P450 1A1 and 1B1. Cancer Res. 3, 3127-3132 (2003).
56. Cavalieri EL, Kumar S, Todorovic R, Higginbotham S, Badawi AF, Rogan EG: Imbalance of estrogen homeostasis in kidney and liver of hamsters treated with estradiol: implications for estrogen-induced initiation of renal tumors. Chem. Res. Toxicol. 14, 1041-1050 (2001).
57. Cavalieri EL, Devanesan P, Bosland MC, Badawi AF, Rogan EG: Catechol estrogen metabolites and conjugates in different regions of the prostate of Noble rats treated with 4-hydroxyestradiol: implications for estrogen-induced initiation of prostate cancer. Carcinogenesis 23, 329-333 (2002).
58. Devanesan P, Santen RJ, Bocchinfuso WP, Korach KS, Rogan EG, Cavalieri EL: Catechol estrogen metabolites and conjugates in mammary tumors and hyperplastic tissue from estrogen receptor α knock out (ERKO)/Wnt 1 mice; implications for initiation of mammary tumors. Carcinogenesis 22, 1573-1576 (2001).
59. Rogan EG, Badawi AF, Devanesan PD et al.: Relative imbalances in estrogen metabolism and conjugation in breast tissue of women with carcinoma: potential biomarkers of susceptibility to cancer. Carcinogenesis 24, 697-702 (2003).
60. Singh S, Chakravarti D, Edney JA et al.: Relative imbalances in the expression of estrogen-metabolizing enzymes in the breast tissue of women with breast carcinoma. Oncol. Rep. 14, 1091-1096 (2005).
61. Liehr JG: Is estradiol a genotoxic mutagenic carcinogen? Endocr. Rev. 21, 40-54 (2000).
62. Zhao Z, Kosinska W, Khmelnitsky M et al.: Mutagenic activity of 4-hydroxyestradiol, but not 2-hydroxyestradiol, in BB rat2 embryonic cells, and the mutational spectrum of 4-hydroxyestradiol. Chem. Res. Toxicol. 19, 475-479 (2006).
63. Saeed M, Zahid M, Gunselman SJ, RoganE, Cavalieri E: Slow loss of deoxyribose from the N7deoxyguanosine adducts of estradiol-3,4-quinone and hexestrol-3′,4′-quinone. Implications for mutagenic activity. Steroids 70, 29-35 (2005).
64. Russo J, Hasan Lareef M, Balogh G, Guo S, Russo IH: Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells. J. Steroid Biochem. Mol. Biol. 87, 1-25 (2003).
65. Russo J, Russo IH: Genotoxicity of steroidal estrogens. Trends Endocrinol. Metab. 15, 211-214 (2004).
66. Lareef MH, Garber J, Russo PA, Russo IH, Heulings R, Russo J: The estrogen antagonist ICI-182,780 does not inhibit the transformation phenotypes induced by 17-b-estradiol and 4-OH estradiol in human breast epithelial cells. Int. J. Oncol. 26, 423-429 (2005).
67. Fernandez SV, Russo PA, Fernbough R et al.: 17β-Estradiol induces transformations and tumorigenesis in human breast epithelial cells. FASEB J. 20, 1622-1634 (2006).
68. Saeed M, Rogan E, Fernandez SV, Sheriff F, Russo J, Cavalieri E: Formation of depurinating N3Adenine and N7Guanine adducts by MCF-10F cells cultured in the presence of 4-hydroxyestradiol. Int. J. Cancer 120, 1821-1824 (2007).
69. Bocchinfuso WP, Korach KS: Mammary gland development and tumorigenesis in estrogen receptor knockout mice. J. Mammary Gland Biol. Neoplasia 2, 323-334 (1997).
70. Bocchinfuso WP, Hively WP, Couse JF, Varmus HE, Korach KS: A mouse mammary tumor virus-wnt-1 transgene induces mammary gland hyperplasia and tumorigenesis in mice lacking estrogen receptor-a. Cancer Res. 59, 1869-1876 (1999).
71. Yue W, Santen RJ, Wang JP et al.: Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis. J. Steroid Biochem. Mol. Biol. 86, 477-486 (2003).
72. Santen RJ, Yue W, Bocchinfuso W et al.: Estradiol-induced carcinogenesis via formation of genotoxic metabolites. In: Advances in Endocrine Therapy of Breast Cancer. Ingle JN, Dowsett M (Eds), Marcel Dekker, NY, USA, 163-177 (2003).
73. Santen R, Cavalieri E, Rogan E et al.: Estrogen mediation of breast tumor formation involves estrogen receptor-dependent, as well as independent, genotoxic effects. Ann. NY Acad. Sci. 1155, 132-140 (2009).
74. Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N. Engl. J. Med. 284, 878-881 (1971).
75. Liehr JG, Ballatore AM, Dague BB, UlubelenAA: Carcinogenicity and metabolic activation of hexestrol. Chem. Biol. Interact. 55, 157-176 (1985).
76. Haaf H, Metzler M: In vitro metabolism of diethylstilbestrol by hepatic, renal and uterine microsomes of rats and hamsters. Effects of different inducers. Biochem. Pharmacol. 34, 3107-3115 (1985).
77. Blaich G, Gottlicher M, Cikryt P, Metzler M: Effects of various inducers on diethylstilbestrol metabolism, drug-metabolizing enzyme activities and the aromatic hydrocarbon (Ah) receptor in male Syrian golden hamster liver. J. Steroid Biochem. 35, 201-204 (1990).
78. Metzler M, McLachlan JA: Oxidative metabolism of the synthetic estrogens hexestrol and dienestrol indicates reactive intermediates. Adv. Exp. Med. Biol. 136(PtA), 829-837 (1981).
79. Jan ST, Devanesan PD, Stack DE et al.: Metabolic activation and formation of DNA adducts of hexestrol, a synthetic nonsteroidal carcinogenic estrogen. Chem. Res. Toxicol. 11, 412-419 (1998).
80. Saeed M, Gunselman SJ, Higginbotham S, Rogan E, Cavalieri E: Formation of the depurinating N3adenine and N7guanine adducts by reaction of DNA with hexestrol-3′,4′-quinone or enzyme-activated 3′- hydroxyhexestrol. Implications for a unifying mechanism of tumor initiation by natural and synthetic estrogens. Steroids 70, 37-45 (2005).
81. Gaikwad NW, Yang L, Muti P et al.: The molecular etiology of breast cancer: evidence from biomarkers of risk. Int. J. Cancer 122, 1949-1957 (2008).
82. Gaikwad NW, Yang L, Pruthi S et al.: Urine biomarkers of risk in the molecular etiology of breast cancer. Breast Cancer: Basic & Clinical Research 3, 1-8 (2009). ■■ Validates the finding that women with breast cancer or at high risk for the disease have significantly higher levels of depurinating estrogen-DNA adducts in their urine than healthy, normal-risk women. These data predict that depurinating estrogen-DNA adducts could become biomarkers for early detection of breast cancer risk and be used in prevention strategies.
83. Markushin Y, Gaikwad N, Zhang H et al.: Potential biomarker for early risk assessment of prostate cancer. Prostate 66, 1565-1571 (2006).
84. Yang L, Gaikwad N, Meza J et al.: Novel biomarkers for risk of prostate cancer. Results from a case-control study. Prostate 69, 41-48 (2009). ■ Men with prostate cancer have significantly higher levels of depurinating estrogen-DNA adducts in their urine compared with healthy men. These data suggest that depurinating estrogen-DNA adducts could serve as potential biomarkers to predict risk for prostate cancer.
85. Gaikwad N, Yang L, Weisenburger DD et al.: Urinary biomarkers suggest that estrogen-DNA adducts may play a role in the etiology of non-Hodgkin lymphoma: Biomarkers 14, 502-512 (2009).
86. Zahid M, Gaikwad N, Rogan EG, CavalieriEL: Inhibition of depurinating estrogen-DNA adducts formation by natural compounds. Chem. Res. Toxicol. 20, 1947-1953 (2007).
87. De Flora S, Cesarone CF, Balansky RM et al.: Chemopreventive properties and mechanisms of N-acetylcysteine. The experimental background. J. Cell Biochem. Suppl. 22, 33-41 (1995).
88. Cao K, Stack DE, Ramanathan R, Gross ML, Rogan EG, Cavalieri EL: Synthesis and structure elucidation of estrogen quinones conjugated with cysteine, N-acetylcysteine and glutathione. Chem. Res. Toxicol. 11, 909-916 (1998).
89. Samuni AM, Chuang EY, Krishna MC et al.: Semiquinone radical intermediate in catecholic estrogen-mediated cytotoxicity and mutagenesis: chemoprevention strategies with antioxidants. Proc. Natl Acad. Sci. USA 100, 5390-5395 (2003).
90. Venugopal D, Zahid M, Mailander PC et al.: Reduction of estrogen-induced transformation of mouse mammary epithelial cells by N-acetylcysteine. J. Steroid Biochem. Mol. Biol. 109, 22-30 (2008). ■■ 4-hydroxyestradiol and estradiol-3,4-quinone transform the normal mouse mammary epithelial cell line E6. N-acetylcysteine, a common antioxidant, inhibited both formation of depurinating estrogen-DNA adducts and malignant transformation of the cells. These results suggest that N-acetylcysteine can be an effective cancer prevention agent.
91. Jang M, Cai L, Udeani O et al.: Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275, 218-220 (1997).
92. Stivala LA, Savio M, Carafoli F et al.: Specific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrol. J. Biol. Chem. 276, 22586-22594 (2001).
93. Lu F, Zahid M, Wang C, Saeed M, Cavalieri EL, Rogan EG: Resveratrol prevents estrogen-DNA adduct formation and neoplastic transformation in MCF-10F cells. Cancer Prev. Res. 1, 135-145 (2008). ■■ The antioxidant resveratrol blocked formation of depurinating estrogen-DNA adducts and neoplastic transformation in estrogen receptor-negative human breast epithelial, MCF-10F, cells. These results suggest that resveratrol can be an effective cancer prevention agent.
94. Zahid M, Gaikwad NW, Ali MF et al.: Prevention of estrogen-DNA adduct formation in MCF-10F cells by resveratrol. Free Radic. Biol. Med. 45, 136-145 (2008).