Accession Number : ADA614393


Title :   Modulation of Estrogen-Depurinating DNA Adducts by Sulforaphane for Breast Cancer


Descriptive Note : Final rept. 15 Sep 2011-14 Sep 2014


Corporate Author : PITTSBURGH UNIV PA


Personal Author(s) : Yang, Li


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a614393.pdf


Report Date : Dec 2014


Pagination or Media Count : 83


Abstract : The goal of this study is to test the hypothesis sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, may alter estrogen metabolism and thus protect against estrogen-mediated DNA damage and carcinogenesis. SFN is a potent inducer of detoxification enzymes such as NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase (GST) via the Keap1-Nrf2 signaling pathway. In summary of the findings, the standards of four heavy isotope labeling estrogen-DNA adducts were successfully synthesized. In cell model, human breast epithelial MCF-10A cells were treated with either vehicle or SFN and either estradiol (E2) or its metabolite 4-hydroxyestradiol (4-OHE2). Estrogen metabolites and depurinating DNA adducts were analyzed by mass spectrometry. Following E2 or 4-OHE2 treatment, the depurinated adducts, 4-OHE1/2-1- N3Adenine and 4-OHE1/2-1-N7Guanine, were reduced by around 60% in both of SFN-treated and siKEAP1-treated cells. However, pharmacologic and genetic approaches have different effects on estrogen metabolism to O-methyl and glutathione conjugates. In animal model, being pre-treated with SFN/Vehicle for one week, ACI rats were implanted E2/Vehicle and treated SFN/Vehicle for 6 weeks. The results show that depurinating estrogen-DNA adducts in urine were significantly inhibited in SFN treatment. In human studies, the urine samples were collected for three continuous days from 14 female subjects in Qidong, China. The results show that there are no significant differences among day 1, day 2 and day 3 for the 4-hydroxy adducts in the urine, which support that one 12-hour urine assay could reasonably reflect current estrogen metabolism.


Descriptors :   *BREAST CANCER , *ESTROGENS , *ISOCYANATES , *THIOCYANATES , CELLS(BIOLOGY) , DEOXYRIBONUCLEIC ACIDS , ENZYMES , GLUTATHIONE , METABOLISM , METABOLITES , TRANSFERASES


Subject Categories : Biochemistry
      Medicine and Medical Research
      Organic Chemistry


Distribution Statement : APPROVED FOR PUBLIC RELEASE