Thesis (Ph.D.) - Cairo University - National Cancer Institute - Department of Cancer Biology

Background: Breast cancer is the most frequently diagnosed cancer in women and ranks second among cancer related deaths in women. Unbalanced estrogen metabolism can lead to increased formation of catechol estrogen quinones, DNA adduct formation, and generation of cancer-initiating mutations. Tumour necrosis factor alpha (TNF-Ü), Leptin, Tamoxifen (TAM), Indole-3-Carbinol (I3C) and All-trans retinoic acid (ATRA) all play roles in breast carcinogenesis either positively or negatively. In this study we investigated the effect of those compounds on the estrogen metabolic pathways in MCF-7, a breast cancer cell line. Results: TNF-Ü and Leptin significantly increased DNA adducts 4-OHE1 [2]-1-N3 adenine and 4-OHE1[2]-1-N7 guanine, upregulated Cytochrome P-450 1B1 (CYP1B1) and downregulated Nicotinamide adenine dinucleotide phosphate-quinoneoxidoreductase1 (NQO1) and Catechol- O-methyl transferase (COMT). TNF-Ü also altered the profile of estrogen metabolites. TAM increased estrone (E1)/17{u2013}Ý-estradiol (E2) ratio, markedly increased the rate of formation of 2-methoxy estradiol (2- MeOE2) and 3-methoxy estrone (3-MeOE1), downregulated CYP1B1 and upregulated NQO1 and COMT levels without affecting DNA adducts. Both ATRA and I3C upregulated CYP1B1, NQO1 and COMT levels while I3C decreased Cytochrome P-450 1A1 (CYP1A1) promoter activity

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