Review Catechol estrogen quinones as initiators of breast and other human cancers: Implications for biomarkers of susceptibility and cancer prevention ☆ Ercole Cavalieri a, ⁎ , Dhubajyoti Chakravarti a , Joseph Guttenplan b , Elizabeth Hart c , James Ingle d , Ryszard Jankowiak e , Paola Muti f , Eleanor Rogan a , Jose Russo g , Richard Santen h , Thomas Sutter i a Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA b New York University Dental and Medical Schools, New York, NY 10032, USA c Hart International, Dallas, TX, USA d Mayo Clinic, Rochester, MN, USA e Department of Chemistry, Kansas State University, Manhattan, KS, USA f Italian National Cancer Institute, Rome, Italy g Fox Chase Cancer Center, Philadelphia, PA, USA h University of Virginia Health System, Charlottesville, VA, USA i Center for Genomic Research, University of Memphis, Memphis, TN, USA Received 11 January 2006; received in revised form 14 March 2006; accepted 19 March 2006 Available online 19 April 2006 Abstract Exposure to estrogens is associated with increased risk of breast and other types of human cancer. Estrogens are converted to metabolites, particularly the catechol estrogen-3,4-quinones (CE-3,4-Q), that can react with DNA to form depurinating adducts. These adducts are released from DNA to generate apurinic sites. Error-prone base excision repair of this damage may lead to the mutations that can initiate breast, prostate and other types of cancer. The reaction of CE-3,4-Q with DNA forms the depurinating adducts 4-hydroxyestrone(estradiol) [4-OHE 1 (E 2 )-1-N3Ade and 4-OHE 1 (E 2 )-1- N7Gua. These two adducts constitute more than 99% of the total DNA adducts formed. Increased levels of these quinones and their reaction with DNA occur when estrogen metabolism is unbalanced. Such an imbalance is the result of overexpression of estrogen activating enzymes and/or deficient expression of the deactivating (protective) enzymes. This unbalanced metabolism has been observed in breast biopsy tissue from women with breast cancer, compared to control women. Recently, the depurinating adduct 4-OHE 1 (E 2 )-1-N3Ade has been detected in the urine of prostate cancer patients, but not in urine from healthy men. Mutagenesis by CE-3,4-Q has been approached from two different perspectives: one is mutagenic activity in the lacI reporter gene in Fisher 344 rats and the other is study of the reporter Harvey-ras gene in mouse skin and rat mammary gland. A → G and G → A mutations have been observed in the mammary tissue of rats implanted with the CE-3,4-Q precursor, 4-OHE 2 . Mutations have also been observed in the Harvey-ras gene in mouse skin and rat mammary gland within 6–12 h after treatment with E 2 -3,4-Q, suggesting that these mutations arise by error-prone base excision repair of the apurinic sites generated by the depurinating adducts. Treatment of MCF-10F cells, which are estrogen receptor-α-negative immortalized human breast epithelial cells, with E 2 , 4-OHE 2 or 2-OHE 2 induces their neoplastic transformation in vitro, even in the presence of the antiestrogen ICI-182,780. This suggests that transformation is independent of the estrogen receptor. The transformed cells exhibit specific mutations in several genes. Poorly differentiated adenocarcinomas Biochimica et Biophysica Acta 1766 (2006) 63 – 78 www.elsevier.com/locate/bbacan Abbreviations: AP, apurinic; BB®, Big Blue; BER, base excision repair; BP, benzo[a]pyrene; CE, catechol estrogen; CE-3,4-Q, catechol estrogen-3,4-quinone; COMT, catechol-O-methyltransferase; CYP, cytochrome P450; CYP19, aromatase; E 1 , estrone; E 2 , estradiol; E 2 -3,4-Q, estradiol-3,4-quinone; ER, estrogen receptor; ERKO, estrogen receptor α-knock out; FASS, field amplified sample stacking; GSH, glutathione; H, Harvey; HBEC, human breast epithelial cells; LC/MS/MS, ultraperformance liquid chromatography/tandem mass spectrometry; LOD, limit of detection; LOH, loss of heterozygosity; MAb, monoclonal antibody; OHE 2 , hydroxyestradiol; 4-OHE 1 (E 2 )-1-N3Ade, 4-hydroxyestrone(estradiol)-1-N3Adenine; 4-OHE 1 (E 2 )-1-N7Gua, 4-hydroxyestrone(estradiol)1-N7Guanine; SCID, severe combined immune depressed; TAM, tamoxifen ☆ Dedicated to Joachim G. Liehr (1942–2003), our colleague, collaborator and friend. ⁎ Corresponding author. Tel.: +1 402 559 7237; fax: +1 402 559 8068. E-mail address: ecavalie@unmc.edu (E. Cavalieri). 0304-419X/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbcan.2006.03.001