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Modulation of Estrogen-Depurinating DNA Adducts by Sulforaphane for Breast Cancer
Annual summary rept. 15 Sep 2011-14 Sep 2012
PITTSBURGH UNIV PA
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Sulforaphane SFN, a bioavailable phytochemical found in young broccoli, is a potent inducer of detoxification enzymes such as NADPHquinone oxidoreductase NQO1 and glutathione-S-transferase GST via the Kelch-like ECH-associated protein 1 Keap1 - Nuclear Factor- E2-related factor Nrf2 signaling pathway. To test the hypothesis that SFN may be an ideal chemoprevention agent to block estrogen-mediated carcinogenesis, we treated the ER-negative, nontumorigenic human breast epithelial MCF10A cell line with either vehicle or SFN 10 M and E2 or 4-OHE2. Results show that NQO1 was up-regulated at the mRNA 2fold, protein 3fold and activity levels 3fold by SFN treatment. Estrogen metabolites and depurinating DNA adducts in the cell culture medium were partially purified by solid phase extraction and then analyzed by UHPLC- ESI-MSMS. Following E2 treatment, the depurinated adducts 4-OHEsub 12-1-N3Ade and 4-OHE 12-1-N7Gua were significantly lower in SFN treated cells compared to vehicle 0.03 0.01 versus 0.07 0.02 pmole106cell, p0.0294 4-OHEsub 12- glutathione conjugates were significantly higher following SFN treatment 1.54 0.37 versus 0.83 0.19 pmole106cell, p0.0015 as were 4-OCH3Esub 12 5.36 0.16 versus 1.81 0.20pmole106cell,p0.0001 levels. Following treatment with the proximate metabolite 4-OHE2, 4-OHEsub 12-1-N3Ade and 4-OHE 12-1-N7Gua were again significantly lower in SFN treated cells compared to vehicle 0.59 0.11 versus 1.42 0.16 pmole106cell, p0.0028 while 4-OHEsub 12-glutathione-conjugates 4.44 0.52 versus 0.87 0.03 pmole106cell,p0.0001 and 4-OCH3Esub 12 levels were significantly higher 195.00 12.33 versus 58.05 1.77pmole106cell, p.00001.
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